HRP20010007A2 - Benzimidazoles, production thereof and use thereof as medicaments - Google Patents

Description

The proposed invention relates to a benzimidazole of the general formula

[image]

to their tautomers, their stereoisomers, their mixtures, prodrugs, their derivatives that instead of a carboxy group contain a group that under physiological conditions has a negative charge, and their salts, especially to their physiologically acceptable salts with inorganic or organic acids or bases that have useful properties.

Compounds of the above general formula I, in which Rc represents a cyano group, are useful intermediates for the production of other compounds of the general formula I, and compounds of the above general formula I, in which Rc denotes one of the following amidino groups, as well as their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives that instead of a carboxy group contain a group that has a negative charge under physiological conditions, and their salts, especially their physiologically acceptable salts with inorganic or organic acids, and their stereoisomers have useful pharmacological properties, especially in terms of antithrombotic activity.

The proposed patent application relates to new compounds of the above general formula I as well as to their preparation, to pharmaceutical preparations containing pharmacologically active compounds, to their production and use.

In the general formula above

Ar represents a phenylene or naphthylene group optionally substituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted in the carbon basic structure with a C1-3-alkyl group,

A represents a C1-3-alkylene group,

B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted with a C1-3-alkyl group where the alkyl group can be mono- or disubstituted with a carboxy group,

Ra represents R1-CO-C3-5-cycloalkyl group in which

R 1 represents a C 1-3 -Alkoxy, amino, C 1-4 -alkylamino or di-(C 1-4 -alkyl)-amino group, where each alkyl group can be substituted with a carboxy group, a 4- to 7-membered cycloalkylenimine or cycloalkenylene- an imino group, which can be substituted with a hydroxy group or can be one or two C1-3-alkyl groups, while one alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylamino-carbonyl, N-(C1-3-alkyl) )-N-(carboxy-C1-3-alkyl)-amino-carbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)- aminocarbonylamino group,

4- to 7-membered cycloalkenylenimino group substituted with a hydroxy group,

a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms,

morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydropiperidino or pyrrole-1-yl group,

R2-CX-C3-5-cycloalkyl group in which

R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, where the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains an imino group optionally substituted with a C1-3-alkyl group, an oxygen or sulfur atom or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent can be substituted with carboxy, by a carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and

X represents an oxygen atom, C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-(C1-3-alkyl) -C2-4-alkanoylhydrazino or C1-3-alkylidene group, each of which can be substituted in the alkyl or alkanoyl part or in the alkyl and alkanoyl groups with a carboxy group,

C1-3-alkyl or C3-5-cycloalkyl group substituted with an imidazole or imidazolone group in which the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl

groups or with one, two or three C1-3-alkyl groups, wherein the substituents can be identical or different and one of the aforementioned alkyl substituents can be simultaneously substituted with a carboxy group or can be substituted in position 2 or 3 with amino, C2 -4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkyl-amino or di-(C1-3-alkyl)-amino group, and

the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and

additionally, the phenyl or pyridine ring can be fused to the aforementioned imidazole or imidazolone ring via two adjacent carbon atoms,

an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with a carboxy group,

C1-4-alkyl group which is substituted

with C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3- alkyl group i

with an isoxazolidinylcarbonyl group optionally substituted with a C1-3-alkyl group, with pyrroline-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrole-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylamino-carbonyl, di-( C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time any alkyl group or alkyl substituent in the above-mentioned C1 -3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms in the C1-4-alkyl group can be completely or partially replaced with fluorine atoms, whereby

R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i

R4 represents a hydrogen atom, C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1 -3-alkyl-Y3 group or

R3 and R4 together with the nitrogen atom between them represent a 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, wherein

Y1 represents a carbon-carbon bond, an oxygen atom, sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH-group and

Y2 represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, where the carbonyl group in the –NH-CO- group is attached to the nitrogen atom of the R3NR4- group, and each of the imino groups, which result from the definition of the groups Y1 and Y2, can be additionally substituted with a C1-3-alkyl or carboxy-C1-3-alkyl group,

C1-3-alkyl or C3-5-cycloalkyl group substituted with R5NR6- group where

R5 represents a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and

R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted with a C2-4-alkanoyl or C5-7-cycloalkanoyl group and with C1 -3-alkyl group substituted with a chlorine, bromine or iodine atom,

Rb represents a hydrogen atom or a C1-3-alkyl group and

Re represents a cyano group or an amidino group optionally substituted with one or two C1-3-alkyl groups.

The carboxy groups mentioned in the definitions of the aforementioned groups can also be replaced with a group that can be converted to a carboxy group in vivo or with a group that under physiological conditions has a negative charge, or

the amino and imino groups mentioned in the definitions of the aforementioned groups may also be substituted with a group that can be cleaved in vivo. Groups of this type are described, for example, in WO 98/46576 and in N.M. Nielson et al., International Journal Pharmaceutics 39, 75-85 (1987).

A group that can be converted to a carboxy group in vivo can be, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, wherein the alcohol group is preferably C1-6-alkanol, phenyl-C1-3-alkanol, C3-9-cycloalkanol , while C5-8-cycloalkanol can be additionally substituted with one or two C1-3-alkyl groups, C3-8-cycloalkanol, where the methylene group in position 3 or 4 is replaced with oxygen or with an imino group substituted with C1- with a 3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group and the cycloalkanol group can be additionally substituted with one or two C1-3-alkyl groups, C4-7-cycloalkenol, C3-5-alkenol, phenyl-C3-5-alkenol, C3-5-alkynol or phenyl-C3-5-alkynol group, provided that no bond to the oxygen atom goes from a carbon atom bearing a double or triple bond, C3 -8-cycloalkyl-C1-3-alkanolic, bicycloalkanolic with a total of 8 to 10 carbon atoms, which d they can also be substituted in the bicycloalkyl group with one or two C1-3-alkyl groups, 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula

Rd-CO-O-(ReCRf)-OH, where

Rd represents a C1-3-alkyl, C1-3-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,

Re represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl or phenyl group i

Rf represents a hydrogen atom or a C1-3-alkyl group,

a group that under physiological conditions has a negative charge can be tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C1-6-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoro- C1-6-alkylsulfonylaminocarbonyl group,

and a group that can be cleaved in vivo from an imino or amino group can be, for example, a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted with fluorine, chlorine, bromine or with iodine atoms, with C1-3-alkyl or by a C1-3-alkoxy group, wherein the substituents can be identical or different, a pyridinoyl group or a C1-6-alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, 3,3,3-trichloropropionyl or allyloxycarbonyl group , C1-16-Alkoxycarbonyl or C1-16-Alkylcarbonyloxy group where hydrogen atoms can be completely or partially replaced by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloreth lcarbonyloxy, alcoholcarbonyloxy, isoalcoholcarbonyloxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, phenyl-C1-6-alkoxycarbonyl group such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, 3 -aminopropionyl group, where the amino group can be mono- or disubstituted with a C1-6-alkyl or C3-7-cycloalkyl group and the substituents can be identical or different, C1-3-alkylsulfonyl-C2-4-alkoxycarbonyl, C1-3- Alkoxy-C2-4-Alkoxy-C2-4-Alkoxycarbonyl, Rd-CO-O-(RdCRf)-O-CO-, C1-6-Alkyl-CO-NH-(RgCRh)-O-CO- or C1- 6-alkyl-CO-O-(RgCRh)-(RgCRh)-O-CO- group, where Rd to Rf are defined as before,

Rg and Rh, which may be identical or different, represent hydrogen atoms or C1-3-alkyl groups.

In addition, the saturated alkyl and alkoxy groups containing more than 2 carbon atoms, mentioned in the above definitions, also include their branched isomers, such as, for example, isoalcohol, tert-butyl, isobutyl group, etc.

Preferred compounds are those compounds of the general formula

[image]

where

A represents a C1-3-alkylene group,

B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted with a C1-3-alkyl group, where the alkyl group can be mono- or disubstituted with a carboxy group,

Ra represents R1-CO-C3-5-cycloalkyl group in which

R1 represents a C1-3-Alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group, where each alkyl group can be substituted with a carboxy group,

4- to 7-membered cycloalkyleneimino or cycloalkenylene-imino group that can be substituted with one or two C1-3-alkyl groups, while the alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3 -Alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3- alkyl)-N-(carboxy-C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3 -(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino ylyl,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonyl- amino group,

4- to 7-membered cycloalkenylenimino group substituted with a hydroxy group,

a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms,

morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydro-piperidino or pyrrole-1-yl group,

R2-CX-C3-5-cycloalkyl group in which

R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, in which the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains imino a group optionally substituted with a C1-3-alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent can be substituted with by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and

X represents an oxygen atom, C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoyl-hydrazino, N-(C1-3- alkyl)-C2-4-alkanoylhydrazino or C1-3-alkylidene group, each of which can be substituted in the alkyl or alkanoyl part or in the alkyl and alkanoyl groups with a carboxy group,

C1-3-alkyl or C3-5-cycloalkyl group substituted with an imidazole or imidazolone group in which

the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, where the substituents can be identical or different and one of the aforementioned alkyl substituents can simultaneously be substituted with a carboxy group or may be substituted in the 2- or 3-position with amino, C2-4-alkanoylamino, C1-3-alkylaniline, N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1- 3-alkyl)-amino group, i

the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and

additionally, the phenyl or pyridine ring can be fused to the above-mentioned imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with a carboxy group,

C1-4-alkyl group which is substituted with C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3-alkyl group and

with an isoxazolidinylcarbonyl group optionally substituted with a C1-3-alkyl group, with pyrroline-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrole-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylamino-carbonyl, di-( C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time any alkyl group or alkyl substituent in the above-mentioned C1 -3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms in the C1-4-alkyl group can be completely or partially replaced with fluorine atoms, where

R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i

R4 represents a hydrogen atom, C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1 -3-alkyl-Y2 group or

R3 and R4 together with the nitrogen atom between them represent a 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group where

Y1 represents a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- group and

Y2 represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, wherein the carbonyl group in the NH-CO- group is connected to the nitrogen atom of the R3NR4- group, and each imino group obtained by the definition of the groups Y1 and Y2 can be additionally substituted with a C1-3-alkyl or carboxy-C1-3-alkyl group,

C1-3-alkyl or C3-5-cycloalkyl group substituted with R5NR6- group in which

R5 represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and

R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group,

a C1-3-alkyl group which is substituted with a C2-4-alkanoyl or C5-7-cycloalkanoyl group and with a C1-3-alkyl group substituted with chlorine, bromine or with an iodine atom,

Rb represents a hydrogen atom or a C1-3-alkyl group and

Rc represents a cyano group or an amidino group which can be substituted with a hydroxy group, with one or two C1-3-alkyl groups, or with one or two C1-8-alkoxycarbonyl groups,

wherein the carboxy, amino and imino groups mentioned in the definition of the aforementioned groups can also be substituted with a group that can be cleaved in vivo, their tautomers, stereoisomers and their salts.

Particularly preferred compounds of the above general formula la are those in which

A represents a C1-3-alkylene group,

B represents an oxygen atom, methylene, imino or N-(C1-3-alkyl)-imino group in which the alkyl group can be substituted with a carboxy group,

Ra represents a C3-5-cycloalkyl group substituted with an R1-CO group in position 1, whereby

R1 represents a C1-3-Alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group in which each alkyl group can be substituted with a carboxy group,

a 4- to 7-membered cycloalkylenimine group that can be substituted with a hydroxy group or with one or two C1-3-alkyl groups, while the alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3 -Alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3- alkyl)-N-(carboxy-C1-3-alkyl)-amino carbonyl, carboxy-C1-3-alkylamino carbons 1 amino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl )-aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3 -alkyl)-aminocarbonyl-amino group,

a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms,

morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydro-piperidino or pyrrole-1-yl group,

C3-5-cycloalkyl group substituted in position 1 with R2-CX- group, where

R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains imino a group optionally substituted with a C1-3-alkyl group, oxygen or a sulfur atom, or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted with by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and

X represents an oxygen atom, a C1-3-alkylimino, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which can be substituted in an alkyl or alkanoyl group with a carboxy group,

C1-3-alkyl group substituted in position l with imidazole or imidazolone group where

the imidazole ring may be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, whereby the substituents may be identical or different and one of the aforementioned alkyl substituents may simultaneously be substituted with a carboxy group or may be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-3-alkanoyl)-C1-3-alkylamino or di-(C1 -3-alkyl)-amino group, i

the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and

additionally, the phenyl or pyridine ring can be fused to the aforementioned imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time, the alkyl substituent can be substituted with a carboxy group,

C1-4-alkyl group which is substituted in position 1 with R3NR4- or R3NR4-C1-3-alkyl group and with pyrrolinecarbonyl, 2,3-dehydro-piperidino-carbonyl, imidazol-1-yl-carbonyl, carboxy, amino-carbonyl , C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, isoxazolidin-1-yl-carbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time each alkyl group or alkyl substituent in the above-mentioned C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms of C1- 3-alkyl groups can be completely or partially replaced with fluorine atoms, whereby

R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i

R4 represents a hydrogen atom, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or

R3 and R4 together with the nitrogen atom located between them form a 4- to 7-membered cycloalkylenimine group optionally substituted in position l with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, where

Y2 represents a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, whereby the carbonyl group in the -NH-CO- group is connected to the nitrogen atom of the R3NR4 group and the imino group formed by the definition of the Y2 group can be additionally substituted with C1- 3-alkyl or carboxy-C1-3-alkyl group,

C1-3-alkyl or C3-5-cycloalkyl group substituted in position l with R5NR6- group, where

R5 represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and

R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkyl and carbonyl group,

C1-3-alkyl group which is substituted with C1-3-alkanoyl or C5-7-cycloalkanoyl group and with C1-3-alkyl group substituted with chlorine, bromine or iodine atom,

Rb represents a C1-3-alkyne group and

Rc represents an amidino group which can be substituted with 2,2,2-trichloroethoxycarbonyl, C1-8- alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or a benzoyl group, while the benzoyl group can be mono- or disubstituted with fluorine, chlorine, bromine or by an iodine atom, with a C1-3-alkyl or C1-3-alkoxy group and the substituents may be identical or different, their C1-3-alkanol esters, tautomers, stereoisomers and their salts.

The most preferred compounds are those compounds of the general formula I in which

A represents a methylene group,

B represents an oxygen atom or an imino group,

Ra represents a cyclopropyl group substituted with the group R1-CO- in position 1, where

R1 represents a pyrrolidino or piperidino group optionally substituted with a methyl or ethyl group, wherein each methyl or ethyl group can be substituted with carboxy, carboxy-C1-3- alkoxy, carboxy-C1-3-alkylamino or N-(C1-3- alkyl)-carboxy-C1-3-alkylamino group,

cyclopropyl group substituted in position 1 with the group R2-CX-, in which

R2 represents a phenyl, pyridyl, pyrazolyl group optionally substituted with a C1-3-alkyl group and

X represents an oxygen atom, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which is a substituent in the alkyl or alkoxy part with a carboxy group,

C1-2-alkyl group substituted in position 1 with an imidazole group, where the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, at wherein the substituents may be identical or different and one of the aforementioned alkyl substituents may be simultaneously substituted with a carboxy group or may be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2- 4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while additionally the phenyl or pyridine ring can be fused to the above-mentioned imidazole ring via two adjacent carbon atoms,

C1-2-alkyl substituted in position 1 with a benzimidazolon-1-yl group, while the imidazolone ring can be substituted with a methyl or ethyl group optionally substituted with a carboxy group,

methyl or ethyl group which is substituted in position 1

with R3NR4- or R3NR4-C1-3-alkyl group and

with a di-(C1-3-alkyl)-aminocarbonyl group, with an isoxazolidin-1-yl-carbonyl group, with a pyrrolidino-carbonyl or piperidino-carbonyl group substituted with a C1-3-alkyl group, while in the aforementioned groups each alkyl group or the alkyl substituent in the above-mentioned groups can be substituted with a carboxy group, whereby

R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i

R4 represents a hydrogen atom, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or

R3 and R4 together with the nitrogen atom located between them form a 4- to 7-membered cycloalkylenimino group optionally substituted with a carboxy group, where

Y2 represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with a C1-3-alkyl group,

C1-2-alkyl group substituted in position 1 with R5NR6-group, where

R5 represents a pyridinyl, phenyl, carbonyl or phenylsulfonyl group and

R6 represents a C1-3-alkyl or carboxy-C1-3-alkyl group,

an n-propyl group substituted in position 3 with a chlorine atom, which is substituted in position 1 with a cyclopentyl-carbonyl group,

a cyclopropyl group substituted in position 1 with a cyclopentylamino group, which is substituted on the nitrogen atom with a carboxy-C1-3-alkylcarbonyl group,

Rb represents a methyl group and

Rc represents an amidino group which, if necessary, can be substituted with a C1-8-alkoxycarbonyl, acetoxy-methyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group,

especially those compounds of general formula Ia in which

A represents a methylene group,

B represents the imino group,

Ra represents a cyclopropyl group substituted with R1-CO- group in position 1, where

R1 represents a pyrrolidino or piperidino group optionally substituted with a methyl or ethyl group, wherein each methyl or ethyl group can be substituted with carboxy, carboxy-C1-3- alkoxy, carboxy-C1-3-alkylamino or with N-(C1- 3-alkyl)-carboxy-C1-3-alkylamino group,

a cyclopropyl group substituted in position 1 with an R2-CX group, wherein

R2 represents a phenyl, pyridyl, pyrazolyl group optionally substituted with a C1-3-alkyl group and

X represents an oxygen atom, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which is substituted in the alkyl or alkoxy part with a carboxy group,

C1-2-alkyl group substituted in position 1 with an imidazole group, whereby the imidazole ring can be substituted with one to three methyl groups or with two methyl groups and one ethyl group, while additionally one of the above-mentioned methyl or ethyl substituents can be substituted at the same time with a carboxy group,

methyl or ethyl group which is substituted in position 1

with R3NR4- or R3NR4-CH2- group i

with di-(C1-3-alkyl)-aminocarbonyl, with pyrrolidino-carbonyl or piperidinocarbonyl group optionally substituted with a C1-3-alkyl group, while in the aforementioned groups each alkyl group or alkyl substituent can be substituted with a carboxy group, where

R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i

R4 represents a C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group, giving

Y2 represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with a C1-3-alkyl group,

Rb represents a methyl group and

Rc represents an amidino group which, if necessary, can be substituted with a C1-8-alkoxycarbonyl, acetoxy-methyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group,

whereby the above-mentioned compounds in which the Ra group is in position 5, their C1-3-alkanol esters, tautomers, stereoisomers and their salts are particularly preferred.

The following compounds are cited as examples of particularly preferred compounds:

(a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-benzimidazole,

(b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole,

(c) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole,

(d) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole,

(e) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl]-benzimidazole,

(f) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and

(g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole,

and their C1-3-alkanol esters, N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines, tautomers, ethereoisomers and their salts.

According to the invention, the compounds of the general formula I are produced by known methods, for example by the following methods:

a) To prepare the compound of the general formula I in which Rc represents a cyano group: the compound of the general formula is cyclized

[image]

which, as necessary, was formed in the reaction mixture, in which formula

Ra, Rb, Ar, and B are defined as above,

Z1 and Z2, which may be identical or different, represent amino, hydroxy or mercapto groups optionally substituted with alkyl groups having from 1 to 6 carbon atoms or

Z1 and Z2 together represent an oxygen or sulfur atom, an imino group optionally substituted with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms.

The cyclization is easily carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin, or in an excess of acylation with that used for the preparation of the compound of general formula II, for example in a suitable nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250°C, and preferably at the boiling temperature of the reaction mixture, if necessary in the presence of a condensing agent as which is phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N-di-cyclohexyl-carbodiimide or as needed in in the presence of a base such as potassium ethoxide or potassium tert-butoxide. However, the cyclization can also be carried out without a solvent and/or condensing agent.

It is particularly advantageous to carry out the reaction in such a way as to produce a compound of the general formula II in the reaction mixture by reducing the corresponding o-nitro compound as necessary in the presence of a carboxylic acid of the general formula

HO-CO-A-B-Ar-CN (III),

in which they are

Ar, and B defined as before, by acylation of the corresponding amino compound as needed formed in the reaction mixture.

b) For the preparation of a compound of the general formula I in which Rs represents R2-CX' -C3-5-cycloalkylene group, where R2 is defined as before, and X' represents one of the imino groups mentioned earlier for X, a compound of the general formula

[image]

in which they are

Rb, RC, Ar, and B defined as earlier i

Ra represents R2-CO-C3-5-cycloalkylene group, where

R2 defined as before reacts with an amine of the general formula

H2X' (V) ,

where

X' represents one of the imino groups mentioned earlier for X.

The reaction is preferably carried out in a solvent such as methanol/toluene, ethanol, isopropanol or xylene and advantageously in the presence of a dehydrating agent such as molecular sieve, sodium sulfate or calcium chloride as needed in the presence of a base such as triethylamine at a temperature between 50 and 100°C, preferably at the temperature of the boiling point of the reaction mixture.

c) For the preparation of a compound of the general formula I in which Ra represents a R2-CX-C1-3-cycloalkylene group, where R2 is defined as before, and X'' represents one of the alkylidene groups mentioned earlier for X, of a compound of the general formula

[image]

in which they are

Rb, Rc, Ar, and B defined as previously i

Ra' represents the R2-CO-C3-5-cycloalkylene group, where

R2 defined as before, reacts with a phosphone of the general formula

Z3-HX" (VI) ,

where

X" represents one of the alkylidene groups mentioned for X i

Z 3 represents a triphenylphosphono or a di-(C 1-3 )-phosphono group, such as a triethoxyphosphono group.

The reaction is preferably carried out under a protective gas in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or dimethyl sulfoxide in the presence of a base such as potassium tert-butoxide, sodium ethoxide or sodium hydride at a temperature between -25 and 50°C, preferably at at temperatures between -15° and room temperature.

d) For the preparation of a compound of the general formula I in which Rc represents an amidino group that can be substituted with one or two C1-3-alkyl groups, a compound of the general formula

[image]

which, as necessary, was formed in the reaction mixture, in which formula are they

Ra, Rb, Ar, and B defined as earlier i

Z4 represents an alkoxy or aralkyl group such as a methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as a methylthio, ethylthio, n-alcoholthio or benzylthio group, reacts with an amine of the general formula

H - R7MR8 (VIII) ,

where

R 7 and R 8 , which may be identical or different, each represent a hydrogen atom or a C 1-3 -alkyl group, or with a salt thereof.

The reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at a temperature between 0 and 150°C, preferably at a temperature between 0 and 80°C, with an amine of general formula VIII or with a corresponding acid addition salt such as for example ammonium carbonate or ammonium acetate.

A compound of general formula VII is obtained, for example, by reacting the appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting the appropriate amide with a trialkyloxonium salt such as triethyloxonium trafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at a temperature between 0 and 50°C, but preferably at 20°C, or the appropriate nitrile with hydrogen sulfide preferably in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and then by alkylating the resulting thioamide with the corresponding alkyl or aralkyl halide.

e) For the preparation of the compound of general formula I in which Ra represents an imidazolidin-2,4-dion-5-yl group, which can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with carboxy or with a C1-3-alkoxycarbonyl group, the compound of the general formula is cyclized

[image]

which, as necessary, was formed in the reaction mixture, in which formula are they

Rb, Ar, and B defined as earlier i

Ra" represents an aminocarbonylamino group substituted in position 3 with a C1-3-alkoxycarbonyl-C1-3-alkyl group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at a temperature between 0 and 50°C, but preferably at 20°C.

f) For the preparation of a compound of the general formula I in which Rc represents a hydroxyamidino group, a nitrile of the general formula

[image]

in which they are

Ra, Rb, Ar and B as defined earlier react with hydroxylamine or its salt.

The reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran, tetrahydrofuran/water, dioxane or dioxane/water at a temperature between 0 and 150°C, preferably at a temperature between 0 and 80°C.

g) For the preparation of a compound of the general formula I in which Ra contains a carboxy group and Rc is defined as earlier or Ra is defined as earlier and Rc represents an amidino group optionally substituted with a hydroxy group or with one or two C1-3-alkyl groups, compound of the general formula

[image]

what formula are they in

Rb, Ar, and B defined as before, a

Ra''' and Rc' have the meaning previously given for Ra and Rc, provided that Ra contains a group which can be converted to a carboxy group by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and Rc is as defined previously, or Rc represents a group which, if necessary, by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis can be converted into an amidino group substituted with a hydroxy group or with one or two C1-3-alkyl groups, and Ra is defined as before, it is translated by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis to a compound of the general formula I in which Ra contains a carboxy group and Rc is defined as earlier or Ra is defined as earlier and Rc represents an amidino group optionally substituted with a hydroxy group or with one or two C1- 3-alkyl groups.

A group that can convert to a carboxy group can be, for example, a carboxyl group protected with a protecting group such as its functional derivative, for example unsubstituted or substituted amides, their esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters that are easily converted by hydrolysis to the carboxyl group, their esters with tertiary alcohols, e.g. tert-butyl ester, which are easily converted to the carboxyl group by acid treatment or thermolysis, and their esters with aralkanols, e.g. benzyl ester, which are easily converted to the carboxyl group by hydrogenolysis.

Hydrolysis is readily carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as is water, water/methanol, water/ethanol, water/isopropanol/methanol, ethanol, water/tetrahydrofuran or water/dioxane at a temperature between -10 and 120°C, for example at a temperature between room temperature and the boiling point of the reaction mixture.

If the compound of formula XI contains, for example, a tert-butyl or tert-butyloxycarbonyl group, it can also be cleaved off by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid according to if necessary in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at a temperature between -10 and 120°C, e.g. at a temperature between 0 and 60°C, or thermally, if necessary in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the temperature of the boiling point of the solvent used, e.g. at a temperature between 40 and 120°C.

If a compound of formula XI contains, for example, a benzyloxy or benzyloxycarbonyl group, it can also be cleaved hydrogenolytically in the presence of a hydrogenolysis catalyst, such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at a temperature between 0 and 50°C, for example at room temperature, and under a hydrogen pressure of 1 to 5 bar.

h) For the preparation of a compound of the general formula I in which Rc represents an amidino group that is substituted with one or two C1-8-alkoxycarbonyl groups or with a group that can be cleaved in vivo, a compound of the general formula I

[image]

in which they are

Ra, Rb, Ar, and B defined as earlier, i

Rc" represents an amidino group, it reacts with a compound of the general formula

Z5-R9(XIII),

where

R9 represents a C1-8-alkoxycarbonyl group or an acyl group of one of the previously mentioned groups that can be cleaved in vivo and

Z 5 represents a nucleophilic leaving group, such as a halogen atom, eg a chlorine, bromine or iodine atom, or a p-nitro-phenyl group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide as necessary in the presence of an inorganic or tertiary organic base, preferably at a temperature between 20°C and the boiling point of the solvent used.

With a compound of general formula XIII in which Z5 represents a nucleophilic leaving group, the reaction is conveniently carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride , potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at a temperature between 0 and 60°C.

If the compound according to the invention of the general formula I containing (R3NR4)-C1-3-alkyl group in which at least one of the groups R3 or R4 represents a hydrogen atom is obtained, it can then be converted with the appropriate isocyanate or carbamoyl halide into the appropriate urea compound of general formula I and/or

if a compound of the general formula I containing an NH2-C1-3-alkyl group is obtained, it can then be converted with a suitable acrylic acid ester into the corresponding 2-(C1-3-alkoxycarbonyl)-ethyl compound of the general formula I and/or

if a compound of the general formula I containing (R3NR4)-C1-3-alkyl group in which each of R3 and R4 represents a hydrogen atom is obtained, it can then be converted with the appropriate dihaloalkane into the corresponding compound of the general formula I in which R3 and R4 together with a nitrogen atom located between them represent a corresponding 4- to 7-membered cycloalkylenimine group and/or

if a compound of the general formula I is obtained in which Rc represents an amidino group, it can then be converted by reaction with a haloacetic acid derivative and then by hydrolysis and decarboxylation into the corresponding amidino compound substituted with one or two methyl groups and/or

if a compound of the general formula I is obtained in which Rc denotes a hydroxyamidino group, it can then be converted into the corresponding amidino compound by catalytic hydrogenation and/or

if a compound of the general formula I is obtained in which Ra contains a carboxy group, it can then be converted by esterification to the corresponding ester.

The subsequent preparation of the corresponding urea compound of general formula I is easily carried out with the appropriate isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and, if necessary, in the presence of a tertiary organic base such as triethylamine at a temperature between 0 and 50°C, preferably at room temperature .

The subsequent preparation of the corresponding 2-(C1-3-alkoxy-carbonyl)-ethyl compound is carried out with the appropriate ester of acrylic acid, preferably in solvents such as methanol, ethanol or isopropanol at a temperature between 50 and 100°C, preferably at the reaction boiling temperature mixtures.

The subsequent preparation of the corresponding 4- to 7-membered cycloalkylenimine compound of the general formula I is conveniently carried out with a suitable dihaloalkane, preferably in a solvent such as methanol, ethanol or isopropanol in the presence of a base such as sodium carbonate at a temperature between 50 and 100°C, preferably at the temperature of the boiling point of the reaction mixtures.

The subsequent alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone as appropriate in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously act as a solvent, or if necessary in the presence of silver carbonate or silver oxide at a temperature between -30 and 100°C, preferably at a temperature between -10 and 80°C.

The subsequent hydrolysis is advantageously carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent as which is water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane and then by decarboxylation in the presence of an acid as mentioned above at a temperature between -10 and 120°C, e.g. at a temperature between room temperature and the temperature of the boiling point of the reaction mixture.

The subsequent esterification is carried out with a suitable alcohol, usually in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, and preferably in an excess of the alcohol used, if necessary in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl- carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, as appropriate in the presence of a base as of potassium carbonate, N-ethyl-di-isopropylamine or N,N-dimethylamino-pyridine, preferably at a temperature between 0 and 150°C, preferably at a temperature from between 0 and 80°C, or with a suitable halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, as necessary in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diiso-propylamine or N-methyl-morpholine, which can simultaneously act as a solvent, or as needed in the presence of silver carbonate or silver oxide at a temperature between -30 and 100°C, but preferably at a temperature between -10 and 80°C.

In the reactions described above, any reactive group present, such as a hydroxy, carboxy, amino, alkylamino or imino group, can be protected during the reaction with conventional protecting groups which are cleaved off after the reaction.

For example, the protecting group for the hydroxy group can be trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl, or tetrahydropyranyl, the protecting group for the carboxy group can be trimethylsilyl, methyl, ethyl, tert.butyl, benzyl, or tetrahydropyranyl, and the protecting group the group for the amino, alkylamino or imino group can be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.

Any protective group used, if necessary, is removed later, for example by hydrolysis in an aqueous solvent, such as water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by cleavage of an ether, for example in the presence of iodotrimethylsilane, at a temperature between 0 and 100°C, preferably at a temperature between 10 and 50°C.

However, the benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved off, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or ice acetic acid, if necessary with the addition of acid such as hydrochloric acid at a temperature between 0 and 50°C, but preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, with preferably 3 to 5 bar.

The methoxybenzyl group can also be cleaved in the presence of an oxidant such as cerium(IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at a temperature between 0 and 50°C, but preferably at room temperature.

However, the 2,4-dimethoxybenzyl group is cleaved preferentially in trifluoroacetic acid in the presence of anisole 1.

The tert-butyl or tert-butyloxycarbonyl group is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, if necessary using a solvent such as methylene chloride, dioxane or ether.

The phthalyl group is cleaved preferably in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at a temperature between 20 and 50°C.

The allyloxycarbonyl group is cleaved by treatment with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess base such as morpholine or 1,3-dimedone at a temperature between 0 and 100°C, preferably at room temperature temperature and under an inert gas, or treatment with a catalytic amount of tris-(triphenylphosphine)-rhodium (I) chloride in a solvent such as aqueous ethanol and, if necessary, in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at a temperature between 20 and 70°C.

The compounds of the general formulas II to XIII, used as starting materials, some of which are known from the literature, can be obtained by methods known from the literature, and in addition, their preparation is described in the examples.

The chemistry of compounds of general formula III is described, for example, by Jack Robinson in J. Chem. Soc. 1941, 744, benzimidazoles are described by Katritzki and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press/ 1984, and Schaumann in Hetarene III, Methoden der organischen Chemie (Houben-Weyl), 4th edition, Verlag Tieme, Stuttgart 1993.

Thus, for example, a compound of general formula II is obtained by acylation of the corresponding o-diamino compound with a corresponding reactive derivative of a compound of general formula III, a compound of general formula IV, VII, IX, X, XI and XII is obtained by cyclization of a correspondingly substituted compound in accordance with a) and then, if necessary, by reduction of each nitro group present in the phenyl group, then by acylation, amidation and/or halogenation.

In addition, the obtained compounds of general formula I can be resolved into their enantiomers and/or diastereomers, as mentioned earlier.

Thus, for example, the obtained compounds of the general formula I which are formed as racemates can be resolved by known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereo-chemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can be separated into their diastereomers on the basis of their physicochemical differences using known methods, e.g. chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they can then be resolved into enantiomers as mentioned above.

Enantiomers are preferably separated by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as esters or amides with a racemic compound, especially with acids and their activated derivatives or alcohols, and by separating obtained diastereomeric mixtures of salts or derivatives, for example on the basis of their differences in solubility, while free antipodes can be separated from pure diastereomeric salts or derivatives by the action of suitable means. Optically active acids that are generally used are, for example, D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolylvic acid, malic acid, mandelic acid, camphorsulfuric acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol may be, for example, (+) or (-)-menthol, and the optically active acyl group in amides may, for example, be (+)- or (-)-menthyloxy-carbonyl.

In addition, the compounds of formula I can be translated into their salts, especially for pharmaceutical use in physiologically acceptable salts with inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, if the new compounds of formula I contain a carboxy group, they can then, if desired, be converted into their salts with inorganic or organic bases, especially for pharmaceutical use into their physiologically acceptable spl. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned earlier, the new compounds of the general formula I and their salts have valuable properties. Thus, compounds of the general formula I in which Rc represents a cyano group are useful intermediate products for the preparation of other compounds of the general formula I, and compounds of the general formula I in which Rc denotes one of the aforementioned amidino groups, and their tautomers, stereoisomers and their physiologically acceptable salts have valuable pharmacological properties, especially in terms of antithrombotic action, which is preferably based on action on thrombin or factor Xa, for example in terms of inhibition of thrombin or inhibition of factor Xa, action in terms of prolongation of aPTT time and inhibitory action against serine-related proteases such as are, for example, trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, dating

A = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride,

B = (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole hydrochloride,

C = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride,

D = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole hydrochloride,

E = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-1-yl-methyl]-benzimidazole hydrochloride,

F = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride and

G = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride

were investigated for their aPTT prolongation effects as follows:

Materials:

- Plasma, from human citrated blood,

- PTT reagent, Boehringer Mannheim (524298),

- calcium solution (0.025 mol/1), Behring Werke, Marburg (ORH 056/57),

- diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),

- Biomatic BIO coagulometer, Desaga, Wiesloch.

Method:

The aPTT time was determined using the Biomatic B10-coagulometer manufactured by Messrs. Desaga.

The test substance was placed in test tubes according to the manufacturer's instructions with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 37°C. The coagulation reaction was initiated by the addition of 0.1 ml of calcium solution. Due to the construction of the apparatus, the time taken for the mixture to coagulate is measured from the moment the calcium solution is added. Mixtures to which 0.1 ml of DBA buffer was added were taken as controls.

By definition, the effective concentration of a substance at which the aPTT time was twice that of the control was determined using a dose/response curve.

The obtained values are listed in the following table:

[image]

The compounds produced according to the invention are well tolerated, as no side effects could be determined at therapeutic doses.

Considering their pharmacological properties, the new compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, for example for the treatment of deep leg veins, for the prevention of reocclusions after bypass operations or angioplasty (PT(C)A) , and occlusions in peripheral arterial diseases such as pulmonary embolism, extended intravascular coagulation, for the prevention of coronary thrombosis, stroke and occlusive diversion. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, for example with rt-PA or streptokinase, for the prevention of long-term restenosis after PT(C)A, for the prevention of metastasis and growth of clot-dependent tumors and fibrin-dependent inflammatory processes , eg in the treatment of pulmonary fibrosis.

The dosage required to achieve such an effect is approximately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg for intravenous administration, and 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg for oral applications, which in any case is given 1 to 4 times a day. For this purpose, the compounds of formula I produced according to the invention can be formulated as necessary together with other active substances, with one or more inert conventional carriers and/or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/-polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as solid fat or suitable mixtures thereof for the production of conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The following examples are intended to illustrate the invention.

Example l

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl) cyclopropyl]-benzimidazole hydrochloride

a) 1-(4-chloro-3-nitro-phenyl)-1-cyclopropanecarboxylic acid

To 350 ml of fuming nitric acid, 50.0 g (0.21 mol) of 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid is added in portions at -25°C. The solution is stirred for 15 minutes at -25°C and then poured onto ice water. The precipitated product is filtered off, washed with water and dried. Yield: 58.5 g (95% of theory), Rf value: 0.45 (silica gel/methylene chloride/methanol = 9.5:0.5)

b) 1-(4-methylamino-3-nitro-phenyl)-1-cyclopropanecarboxylic acid

20.0 g (0.083 mol) of 1-(4-chloro-3-nitrophenyl)-1-cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% in H2O) are heated for 5 hours at 80°C in a pressure vessel. The contents are evaporated to dryness, dissolved in water and acidified with glacial acetic acid. The precipitated product is sucked off, washed with water and dried.

Yield: 16.9 g (93% of theoretical),

Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1)

c) 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-nitro-N-methyl-aniline

2.4 g (0.01 mol) of 1-(4-methylamino-3-nitro-phenyl)-1-cyclopropanecarboxylic acid is dissolved in 50 ml of dimethylformamide and after the addition of 3.2 g (0.01 mol) of O -(benzo-triazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) pyrrolidine and 1.1 g (0.01 mol) N- methyl-morpholine is stirred for 20 hours at room temperature. The solvent is distilled off and the residue is chromatographed on silica gel, washing with methylene chloride. The desired fractions are concentrated by evaporation, triturated with ether, filtered off with suction and dried.

Yield: 1.8 g (61% of theoretical), Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1)

c) 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-amino-N-methyl-aniline

1.8 g (6.2 mmol) of 4-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-2-nitro-N-methyl-aniline was dissolved in 40 ml of methanol and 40 ml of methylene chloride and after addition of 0.4 g of palladium on activated carbon (10%) is hydrogenated for 4 hours at room temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation. Yield: 1.6 g (100% of theoretical),

Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1)

e. 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-(4-cyano-phenyl)aminomethyl]carbonylamino-N-methyl-aniline

It is produced analogously to example Ic from 4-[1-(pyrrolidin-1-yl-carbonyl) cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N', of N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Utilization: 66% of the theoretical,

Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1)

f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole

1.7 g (0.004 mol) of 4-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline is refluxed for 2 hours in 7 ml of glacial acetic acid. acid. The solvent is distilled off, the residue is dissolved in water and extracted with methylene chloride. The organic phase is dried, concentrated by evaporation and then chromatographed on silica gel, washing with methylene chloride + 2 to 3% methanol. Yield: 1.0 g (62% of theoretical),

Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1)

g. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole is dissolved in 50 ml of saturated ethanolic hydrochloric acid and it is stirred for 5 hours at room temperature. The solvent is distilled off, the residue is dissolved in 50 ml of absolute ethanol and mixed with 2.3 g (25 mmol) of ammonium carbonate. After 60 hours at room temperature, the mixture is evaporated to dryness. The residue is chromatographed on silica gel, washing with methylene chloride/methanol (7:1). Utilization: 700 mg (62% of the theoretical),

Rf value: 0.61 (silica gel; methylene chloride/methanol = 4:1)

C24H28N60 x HCl (416.54/453.0)

mass spectrum: (M+H)* = 417

The following compounds were obtained analogously to example 1:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-methyl-piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 45% of the theoretical

Rf value: 0.25 (silica gel; methylene chloride/methanol = 4:1)

C26H32N6O x HCl (444.59/481.05)

mass spectrum: (M+H)+ = 445

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 57% of the theoretical,

Rf value: 0.23 (silica gel; methylene chloride/methanol = 4:1)

C25H30N6O x HCl (430.56/467.93)

mass spectrum: (M+H)+ = 431

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(4-methyl-piperazin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 32% of the theoretical

Rf value: 0.26 (silica gel; methylene chloride/methanol/ammonia = 2:1:0.25)

C25H31N7O x HCl (445.58/482.04)

mass spectrum: (M+H)+ = 446

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2,3-dihydro-indolin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 60% of the theoretical

Rf value: 0.34 (silica gel; methylene chloride/methanol = 4:1)

C28H28N6O x HCl (464.58/501.04)

mass spectrum: (M+H) + =465

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((2-ethoxy-carbonylethyl)-piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 85% of the theoretical

Rf value: 0.57 (silica gel; methylene chloride/methanol = 4:1)

C30H38N6O3 x HCl (530.67/567.13)

mass spectrum: (M+H)+ =531

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((2-ethoxy-carbonylethyl)-pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride

Utilization: 60% of the theoretical

C29H36N6O3 x HCl (516.64/553.10)

mass spectrum: (M+H)+ = 517

(M+2H)++ = 259

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(N-(2-ethoxycarbonylethyl)-N-methyl-aminomethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole- hydrochloride

Utilization: 65% of the theoretical

C31H41N7O3 x HCl (559.72/596.18)

mass spectrum: (M+H) + = 560

(M+2H)++ = 280.6

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(2-ethoxy-carbonylmethyloxymethyl)-pyrrolidin-1-yl-carbonyl]-cyclopropyl]benzimidazole hydrochloride

Utilization: 61% of the theoretical

Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1% glacial acetic acid)

C29H36N6O4 x HCl (532.66/569.11)

mass spectrum: (M+H) + = 533

(M+2H)++ = 267

Example 2

2-(4-amidinophenylaminomethyl)-1-methyl-5-(1-cyclopentyl-carbonyl-3-chloro-n-propyl)-benzimidazole hydrochloride

a. 4-[1-cyclopentyl-carbonyl)-cyclopropyl-chlorobenzene

2.4 g (0.1 mol) of magnesium shavings are suspended in 10 ml of ether. After the knife-tip addition of iodine, 14.9 g (0.1 mol) of bromocyclopentane is added slowly dropwise to 40 ml of ether and the reaction is started with initial gentle heating. After the addition is complete, the mixture is refluxed for 30 minutes. A solution of 14.0 g (0.08 mol) of 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile in 75 ml of ether was then added and refluxed for another 3 hours. The reaction solution was poured onto ice water, the pH was adjusted to 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and washed with petroleum ether/ethyl acetate (19:1 and 15:1).

Yield: 3.0 g (12% of theoretical),

Rf value: 0.58 (silica gel; petroleum ether/ethyl acetate = 4:1)

b. 4-[1-cyclopentyl-carbonyl)-cyclopropyl]-2-nitro-chloro-benzene

It is produced analogously to example 1a from 4-[1-(cyclopentylcarbonyl)cyclopropyl]chlorobenzene and fuming nitric acid.

Utilization: 87% of the theoretical,

Rf value: 0.60 (silica gel; petroleum ether/ethyl acetate = 9:1)

c. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-N-methyl-aniline

It is produced analogously to example 1a from 4-[1-cyclo-pentyl-carbonyl)-cyclopropyl]-2-nitro-chlorobenzene and an aqueous solution of methylamine. Utilization: 18% of the theoretical,

Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1)

d. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methyl-aniline

2.3 g (7.9 mmol) of 4-[1-(cyclopentylcarbonyl)-cyclopropyl]-2-nitro-N-methyl-aniline were dissolved in 125 ml of ethyl acetate and 25 ml of ethanol and after the addition of 1.0 g of Raney nickel is hydrogenated for 1.5 hours at room temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation. Yield: 2.0 g (98% of theoretical),

Rf value: 0.15 (silica gel; methylene chloride/ethanol = 19:1)

e. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-(4-cyanophenyl-aminomethyl-carbonylamino)-N-methyl-aniline

It is produced analogously to example 1c from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium -tetrafluoroborate/4-cyano-phenylglycine and triethylamine in dimethylformamide.

Utilization: 96% of the theoretical,

Re value: 0.54 (silica gel; methylene chloride/ethanol = 19:1)

f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(cyclopentylcarbonyl)-cyclopropyl]-benzimidazole

It was produced analogously to example 1c from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-(4-cyanophenyl-aminomethyl-carbonylamino)-N-methyl-aniline in glacial acetic acid. Utilization: 53% of the theoretical,

Rf value: 0.46 (silica gel; methylene chloride/ethanol = 19:1)

g. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1-cyclopentyl-carbonyl-3-chloro-n-propyl)-benzimidazole hydrochloride

It is produced analogously to example 1g from 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(cyclopentyl-carbonyl)-3-chloro-n-propyl)-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 61% of theoretical, C25H30ClN5O x HCl (452.00/488.56)

mass spectrum: (M+H)+ = 452/4 (Cl))

Example 3

(E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxylmino)-methylene]cyclopropyl]-benzimidazole hydrochloride

a. 1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-benzene

A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether was added dropwise at -40 to -50°C to 100 ml of butyllithium (1/6 M in hexane) and then stirred for 20 minutes at -40°C. The mixture was then cooled to -60°C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane-carbonitrile in 125 ml of ether was added dropwise. When everything is added, the reaction mixture is warmed to room temperature and stirred for 5 hours. The suspension is mixed with 20% hydrochloric acid and heated for 30 minutes at 100°C. When cooled, the mixture is adjusted to pH 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on aluminum oxide, eluting with petroleum ether/ethyl acetate (9:1).

Yield: 14.0 g (46% of theoretical),

Rf value: 0.27 (alumina; petroleum ether/ethyl acetate = 9:1)

b. 1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-nitrobenzene

It is produced analogously to example 1a from 1-[(pyridin-3-yl)-carbonyl]cyclopropyl-benzene and fuming nitric acid. Utilization: 53.7% of the theoretical

Rf value: 0.29 (alumina; petroleum ether/ethyl acetate = 4:1)

c. 1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-alanine

It was prepared analogously to example 1a from 1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-nitrobenzene and Raney nickel in ethyl acetate/ethanol.

Utilization: 94% of the theoretical

Rf value: 0.51 (silica gel; methylene chloride/ethanol = 19:1)

d. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-trifluoroacetaniline

8.0 g (33.5 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]-cyclopropyl]-aniline is dissolved in 100 ml of chlorobenzene and after the addition of 15 ml of trifluoroacetic anhydride, the mixture is stirred for two hours at 110°C. The solvent is distilled off, the residue is mixed with petroleum ether/ether (9:1), sucked off and dried.

Yield: 10.0 g (88% of theoretical),

Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1)

e. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-1-trifluoroacetylaniline

1.7 g (5 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-trifluoroacetylaniline was added gradually to 13 ml of conc. sulfuric acid and 16 ml of 65% nitric acid at -5°C. The mixture is then stirred for a further 30 minutes without cooling, poured onto ice water and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and washed with methylene chloride/ethanol (50:1 and 25:1). The desired fractions are concentrated by evaporation, triturated with ether/petroleum ether, suction filtered and dried.

Yield: 1.2 g (75% of theoretical),

Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1)

f. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methyl-aniline

1.15 g (3.0 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]-cyclopropyl]-2-nitro-trifluoroacetylaniline is dissolved in 50 ml of acetone and after the addition of 2.0 g of potassium carbonate and 0.8 ml of methyl iodide refluxed for two hours. The insoluble substance is filtered off and the solution is evaporated. The residue is chromatographed on silica gel, washing with petroleum ether/ethyl acetate (1:1 and 1:4).

Yield: 0.88 g (75% of theoretical),

Rf value: 0.38 (silica gel; petroleum ether/ethyl acetate = 1:1)

g. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-methyl-aniline

7.4 g (18.8 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]-cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methyl-aniline was stirred for one hour at 30° C in 200 ml of a 20% solution of potassium hydroxide. Then the mixture is diluted with isopropanol, the organic phase is separated, 10.0 g of aluminum oxide is added and the resulting mixture is evaporated to dryness. The residue is chromatographed on aluminum oxide, eluting with petroleum ether/ethyl acetate (4:1 and 1:1). Yield: 2.6 g (47% of theoretical),

Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate = 1:1)

h. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline

It was prepared analogously to example 2d from 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-methyl-aniline and Raney nickel in ethyl acetate/ethanol. Utilization: 98% of the theoretical

Rf value: 0.51 (silica gel; methylene chloride/ethanol = 19:1)

and . 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-(4-cyano-phenyl)-aminomethylcarbonylamino-N-methyl-aniline

It was produced analogously to example Ic from 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N of ',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.

Utilization: 97% of the theoretical,

Rf value: 0.48 (silica gel; methylene chloride/ethanol = 19:1)

k. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-carbonyl] cyclopropyl]-benzimidazole

It was produced analogously to example 1f from 4-(pyridin-3-yl-carbonyl)cyclopropyl-2-(4-cyanophenyl)-aminomethylcarbonyl-amino-N-methyl-aniline in glacial acetic acid. Utilization: 76% of the theoretical,

Rf value: 0.52 (silica gel; methylene chloride/ethanol with 19:1)

1. (E/Z)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(carboxymethyloxylamino)methylene]-cyclopropyl]benzimidatol

1.6 g (4.0 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-benzimidazole, 3.0 g (12 rammol ) of carboxy-methoxylamine hemihydrate, 0.84 ml of triethylamine, 12 g of molecular sieve 3A and 12 g of molecular sieve 4 A are refluxed for 12 hours in 80 ml of methanol and 40 ml of toluene. The molecular sieve is then filtered off and the filtrate is concentrated by evaporation. The residue is mixed with water, filtered and dried. The crude product is chromatographed on silica gel, eluting with methylene chloride/ethanol/glacial acetic acid (25:1:0 and 8:2:0.2).

Yield: 0.9 g (48% of theoretical),

Rf value: 0.34 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2)

m. (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxylmino)-methylene]cyclopropyl-1-benzimidazole hydrochloride

It was produced analogously to example 1 g from (E/Z)-2-(4-cyanophenyl-aminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(ethoxycarbonylmethyloxylmino)methylene]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 60% of the theoretical

Rf value: 0.28 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2)

C29H32N7O3 x HCl (525.62/562.09)

mass spectrum: (M+H)+ = 526

The following compounds were obtained analogously to example 3:

(1) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(ethoxycarbonylmethyloxylmino)-methylene]cyclopropyl] benzimidazole hydrochloride

Utilization; 52% of the theoretical,

Rf value: 0.21 (silica gel; methylene chloride/ethanol/

glacial acetic acid = 8:2:0.2)

C29H31N7O3 x HCl (525.62/562.09)

mass spectrum: (M+H)+ = 526

(2) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phenyl-(ethoxycarbonylmethyloxylamino)-methylene]-cyclopropyl]-benzimidazole hydrochloride

Utilization: 18% of the theoretical,

C30H32N6O3 x HC1 (524.63/561.09)

mass spectrum: (M+H)+ = 525

(M-H+HC1)- = 559/61 (Cl)

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1-methyl-pyrazol-5-yl-carbonyl)cyclopropyl]benzimidazole hydrochloride

Utilization: 10% of the theoretical,

C24H25N7O x HC1 (427.517 463.97)

mass spectrum: (M+H)+ = 428 (M+H+HCl)- = 464/6 (Cl)

(4) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(1-methyl-pyrazol-5-yl-(ethoxycarbonylmethyloxylmino)-methylene]cyclopropyl]-benzimidazole hydrochloride

Utilization: 80% of the theoretical

Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1% glacial acetic acid)

C28H32N8O3 x HCl (528.63/565.08)

mass spectrum: (M+H) + = 529

(5) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phenyl-(3-ethoxycarbonyl-n-propyloxylmino)methylene]-cyclopropyl]-benzimidazole dihydrochloride

Utilization: 47% of the theoretical,

Rf value: 0.06 (silica gel; methylene chloride/methanol = 9:1)

C32H36N6O3 x HCl (552.69/625.60)

mass spectrum: (M+H)+ = 553

Example 4

(E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxylamino)methylene]-cyclopropyl]-

benzimidazole hydrochloride

150 mg of (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl-(ethoxycarbonylmethyloxylmino)methylene]-cyclopropyl]-benzimidazole hydrochloride and 2.5 ml 2N sodium hydroxide solution is stirred for 5 hours in 10 ml of ethanol at room temperature. The alcohol is distilled off and the residue is adjusted to pH 5 with hydrochloric acid. The crystalline product is filtered off with suction, washed with water and dried. Yield: 46% of the theoretical,

Rf value: 0.10 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.1)

C27H27N7O3 x HCl (497.58/534.05)

mass spectrum: (M+H)+ = 498

(M+Na)+ = 520

The following compounds were obtained analogously to example 4:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-piperidin-1-yl-carbonyl]cyclopropyl]-benzinidazole

-hydrochloride

Utilization: 94% of the theoretical,

Rf value: 0.57 (RP 18 reverse phase; methanol/5% sodium chloride solution = 3:2)

C28H34N6O3 x HCl (502.62/539.08)

mass spectrum: (M+H) + = 503

(M+Na)+ = 525

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 98% of the theoretical,

Rt value: 0.73 (RP 18 reverse phase; methanol/5%-tna

sodium chloride solution = 1:2)

C26H33N7O3 x HCl (491.60/564.54)

mass spectrum: (M+H)+ = 492

(M+H)+ = 247

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-carboxy-propionylamino)-1-(ethoxycarbonyl)-ethyl]-benzimidazole

-hydrochloride

Utilization: 98% of the theoretical,

Rf value: 0.70 (RP 8; methanol/5% sodium chloride solution = 1:2)

C25H30N6O5 x HCl (494.55/531.05)

mass spectrum: (M+H)+ = 495

(2M+H)+ = 989

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-methyl]

- benzimidazole hydrochloride

Utilization: 87% of the theoretical,

C24H29N7O3 x HCl (463.54/500.04)

mass spectrum: (M+H)+ =464

(M+2H) + = 232.6

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]

- benzimidazole hydrochloride

Utilization: 94% of the theoretical,

C27H32N6O3 x HCl (488.59/525.05)

mass spectrum: (M+H)* = 489

(M+Na)+ =511

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-methyl]

-benzylnidazole hydrochloride

Utilization: 49% of the theoretical,

C25H29N7O4 x HCl (491.55/528.01)

mass spectrum: (M+H)* = 492

(M+H+Na)++ = 257.7

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

-benzylnidazole hydrochloride

Utilization: 92% of the theoretical,

C26H31N7O4 x HC1 (505.58/542.04)

mass spectrum: (M+H)+ = 506

(M+H+Na)++ = 264.7

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3-carboxymethyl-imidazolin-2,4-dion-5-yl)-benzimidazol

-hydrochloride

Utilization: 88% of the theoretical,

C22H23N7O4 x HC1 (449.47/485.94)

mass spectrum: (M+H)+ = 450

(M+2Na)++ = 247.7

(9) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(carboxymethyloxylamino)methylene]

-cyclopropyl]-benzimidazole hydrochloride

Utilization: 54% of the theoretical,

C27H27N7O3 x HC1 (497.56/534.09)

mass spectrum: (M+H) + = 498

(M+Na) + = 520

(10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(N-(2-carboxyethyl)-N-methyl-aminomethyl)-pyrrolidin-1-yl

-carbonyl]-cyclopropyl]-benzimidazole hydrochloride

Utilization: 100% of the theoretical,

C29H37N7O3 x HCl (531.66/568.12)

mass spectrum: (M+H)+ = 532

(M-H)- = 530

(11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-carboxy-ethyl)-N-(2-pyridyl)-aminomethyl]-benzimidazole

-hydrochloride

Utilization: 91% of the theoretical,

C25H27N7O2 x HC1 (457.54/493.96)

mass spectrum: (M+H)+ = 458

(12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(N-benzenesulfonyl-N-carboxymethyl-aminomethyl)-benzimidazole

-hydrochloride

Utilization: 84% of the theoretical,

C25H26N6O4S x HCl (506.59/543.06)

mass spectrum: (M+H)+ = 507

(13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxy-ethyl)-benzimidazol-1-yl-methyl]-benzimidazole

-hydrochloride

Utilization: 76% of the theoretical,

C27H27N7O2 x HCl (481.56/518.05)

mass spectrum: (M+H)+ = 482

(M+2H)2+ = 242

(M+Na)+ = 504

(M+H+Na)2+ = 253

(M-H+2Na)+ - 526

(M+2Na)2+ = 264

(14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(2-methyl-4-carboxy-imidazol-1-yl-methyl)-benzimidazole hydrochloride

Utilization: 61% of the theoretical,

C22H23N7O2 x HCl (417.47/453.92)

mass spectrum: (M+H) + = 418

(15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[3-(3-carboxy-n-propyl)-benzimidazol-2-on-1-yl-methyl]

- benzimidazole hydrochloride

Utilization: 86% of the theoretical,

C28H29N7O3 x HCl (511.59/548.04)

mass spectrum: (M+H)+ = 512

(M+Na)+ = 534

(M+H+Na)2+ = 267.7

(M+Na)2+ = 278.8

(16) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[3-(2-carboxy-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl-methyl]

- benzimidazole hydrochloride

Utilization: 83% of the theoretical,

C26H26N8O3 x HCl (498.55/535)

mass spectrum: (M+H)+ = 499

(M+Na)+ =521

(M-H)- = 497

(2M-H)- = 995

(17) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-1-yl-methyl]-benzimidazole

-hydrochloride

Utilization: 68% of the theoretical,

Rf value: 0.70 (RP 18 reverse phase; methanol/5% sodium chloride solution = 6:4)

C25H29N7O2 x HCl (459.56/496.01)

mass spectrum: (M+H)+ = 460

(M+Na)+ = 482

(M+H+Na)2+ = 241

(18) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phenyl-(carboxymethyloxyimino)methylene]cyclopropyl]

- benzimidazole dihydrochloride

Utilization: 70% of the theoretical,

C28H28N6O3 x HCl (496.57/569.5)

mass spectrum: (M+H) + = 497

(M-H) + = 495

(19) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-(carboxymethylidene)-methylene]cyclopropyl]

- benzimidazole hydrochloride

Utilization: 37% of the theoretical,

Rf value: 0.45 (RP 18 reverse phase; methanol/5% sodium chloride solution = 6:4)

C27H26N6O2 x HCl (466.55/503.0)

mass spectrum: (M+H)+ =467

(20) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(1-methylpyrazol-5-yl)-(carboxymethyloxylamino)-methylene]

-cyclopropyl]-benzimidazole hydrochloride

Utilization: 30% of the theoretical,

Rf value: 0.25 (RP 18 reverse phase; (5% sodium chloride solution/methanol = 1:1)

C26H28N8O3 x HCl (500.58/537.03) mass spectrum: (M+H)+ = 501

(M-H)- = 499

(M+C1)+ = 535/537 (Cl)

(21) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[phenyl-(3-carboxy-n-propyloxyimino)methylene]-cyclopropyl]

- benzimidazole dihydrochloride

Utilization: 37% of the theoretical,

Rf value: 0.35 (RP 18 reverse phase; 5% sodium chloride solution/methanol = 3:2)

C30H32N6O3 x HCl (524.64/597.55)

mass spectrum: (M+H)+ 525

Example 5

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)

a. 5-(4-chlorophenyl)-imidazolidine-2,4-dione

15.0 g (0.11 mol) of 4-chlorobenzaldehyde, 51.3 g (0.53 mol) of ammonium carbonate and 7.6 g (0.12 mol) of potassium cyanate are mixed in 150 ml of water and 150 ml of methanol 18 hours at 55°C. The solvent is distilled off, the residue is dissolved in water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.

Yield: 8.6 g (38% of theoretical), melting point: 215°C.

b. 5-(4-chloro-3-nitro-phenyl)-imidazolidine-2,4-dione

It is produced analogously to example 1a from 5-(4-chlorophenyl)-imidazolidin-2,4-dione and fuming nitric acid.

Utilization: 52% of the theoretical,

Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1)

c. 5-(4-chloro-3-nitro-phenyl)-imidazolinine hydrochloride

560 mg (2.2 mmol) of 5-(4-chloro-3-nitro-phenyl)-imidazolidine-2, 4-dione is refluxed for 24 hours in 20 ml of semiconc. hydrochloric acid. The solvent is distilled off, the residue is dissolved in water, filtered to remove insoluble material and concentrated by evaporation. The residue is dissolved three times in ethanol, evaporated to dryness, triturated with ether, sucked off and dried.

Yield: 380 mg (65% of theoretical), melting point: 186°C.

d. 4-chloro-3-nitro-N-tert.butyloxycarbonyl-phenylalanine

5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine hydrochloride are dissolved in 50 ml of dioxane and 25 ml of water and, after the addition of 5.5 ml (39.1 mmol) of triethylamine and 4 .8 g (21.3 mmol) of di-tert.butyl-dicarbonate, stirred for 18 hours at room temperature. The mixture is then diluted with a 0.5 M solution of potassium hydrogen sulfate and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.

Yield: 6.3 g (100% of theoretical),

Rf value: 0.20 (silica gel; methylene chloride/methanol = 9:1)

e. 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-ethanone

It is produced analogously to example 1c from 4-chloro-3-nitro-N-tert.butyloxycarbonyl-phenylalanine, O-(benzotriazol-1-yl)

-N,N,N',N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-diisopropylamine in tetrahydrofuran.

Yield: 68% of theoretical, melting point: 203°C.

f. 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonyl-amino-1-(pyrrolidin-1-yl)-ethanone

It was produced analogously to example 1b from a solution of 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)ethanone and methylamine.

Utilization: 76% of the theoretical,

Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate = 1:1)

g. 2-(4-methylamino-3-aminophenyl)-2-tert.butyloxycarbonyl-amino-1-(pyrrolidin-1-yl)-ethanone

It was produced analogously to example 1d from 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-ethanone and palladium on activated carbon in methylene chloride/ethanol.

Utilization: 100% of theoretical

Rf value: 0.12 (silica gel; cyclohexane/ethyl acetate = 1:1)

h. 2-[4-methylamino-3-(4-cyanophenylaminomethyl-carbonyl-amino)-phenyl]-2-tert.butyloxycarbonylamino-1-(pyrrolidine-

1-yl)-ethanone

It was produced analogously to example 1c from 2-(4-methylamino-3-aminophenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-ethanone, O-(benzotriazol-1-yl)-N,N, N',N'-tetramethyl-uronium tetrafluoroborate, 4-cyano-phenylglycine and triethyl-amine in tetrahydrofuran.

Utilization: 100% of the theoretical,

Rf value: 0.50 (silica gel; methylene chloride/methanol = 9:1)

and . 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-aminomethyl]-benzimidazole

It was produced analogously to example 1f from 2-[4-methyl-amino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-ethanone in glacial acetic acid.

Utilization: 30% of the theoretical

Rf value: 0.19 (silica gel; methylene chloride/methanol = 9.5:0.5)

k. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-aminomethyl]-benzimidazole hydrochloride

It is produced analogously to example 1g from 2-(4-cyano-phenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-aminomethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 27% of the theoretical,

C22H27N7O x HCl (405.50/441.96)

mass spectrum: (M+H)+ = 406

The following compounds were obtained analogously to example 5:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-acetyl-aminomethyl]-benzimidazole

-hydrochloride

Utilization: 29% of the theoretical,

C24H29N7O2 x HCl (447.54/484.54)

mass spectrum: (M+H)+ = 448

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-N-methyl-amino

-methyl]-benzimidazole hydrochloride

Utilization: 74% of the theoretical,

C28H37N7O3 x HC1 (519.65/556.11)

mass spectrum: (M+H)+ =520

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(ethoxycarbonylmethyl)-aminomethyl]

- benzimidazole hydrochloride

Utilization: 76% of the theoretical,

C26H33N7O3 x HCl (491.59/528.05)

mass spectrum: (M+H)+ = 492

(M+2H)++ = 246.7

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N,N-di-(ethoxycarbonylmethyl)-aminomethyl]

- benzimidazole hydrochloride

Utilization: 51% of the theoretical,

C30H39N7O5 x HCl (577.68/614.14)

mass spectrum: (M+H)+ = 578

(M+Na)+ = 600

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(ethoxycarbonylmethylcarbonyl)-aminomethyl]-benzimidazole hydrochloride

Utilization: 29% of the theoretical,

C27H33N7O4 x HCl (519.60/556.06)

mass spectrum: (M+H)+ = 520

(M+2H)++ = 260.7

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]

- benzimidazole hydrochloride

Utilization: 84% of the theoretical,

C27H35N7O3 x HCl (505.62/542.62)

mass spectrum: (M+H)+ = 506

(M+2H)++ = 253.7

Example 5

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl]benzimidazole hydrochloride

a. 5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidine-2,4-dione

To 50 ml of fuming nitric acid at -25°C to -35°C, 10.0 g (4.45 mmol) of 5-(4-chloro-phenyl)-5-methyl-imidazolidin-2,4- part. After 45 minutes at -25 to -20°C, the reaction mixture is poured onto ice water. The crystalline product is suctioned off, washed with water and dried. Yield: 10.5 g (100% of theoretical),

melting point: 173-178°C

Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate = 1:1)

b. 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid

10.5 g (0.044 mol) of 5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidine-2,4-dione was refluxed for 5 days in 200 ml of dioxane and 700 ml of 6N hydrochloric acid. The solution is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The aqueous phase is concentrated by evaporation, mixed with toluene and evaporated to dryness. The residue is triturated with ether, suction filtered and dried.

Yield: 6.8 g (63% of theory),

Rf value: 0.24 (RP reverse phase, 5% NaCl/methanol solution = 1:1)

c. 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitrophenyl)-propionic acid

It is produced analogously to example 5d from 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid, di-tert.butyl pyrocarbonate and triethylamine in dioxane.

Yield: 9.6 g (100% of theoretical),

Rf value: 0.31 (RP 8 reverse phase, 5% NaCl/methanol solution = 1:2)

d. 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone

It is produced analogously to example 1c from 2-tert.butyl-oxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid, O-(benzotriazol-1-yl)-N,N,N',N' -tetramethyluronium tetrafluoroborate, pyrrolidine and N-methylmorpholine in dimethylformamide.

Utilization: 94% of the theoretical,

Rf value: 0.11 (silica gel; cyclohexane/ethyl acetate = 1:1)

e. 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxy-carbonylamino-1-(pyrrolidin-1-yl)-propanone

It was produced analogously to example 1b from a solution of 2-(4-chloro-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone and methylamine in dimethylformamide at 160°C.

Rf value: 0.79 (silica gel; ethyl acetate/ethanol = 9:1)

f. 2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-amino-1-(pyrrolidin-1-yl)-propanone

It was prepared analogously to example 1d from 2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone and palladium on activated carbon/hydrogen in methanol.

Utilization: 100% of the theoretical,

Rf value: 0.63 (silica gel; ethyl acetate/ethanol = 9:1)

g. 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonyl-amino)-phenyl]-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone

It was produced analogously to example 1c from 2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone, O-(benzotriazol-1-yl)-N, of N,N',N'-tetra-methyl-uronium tetrafluoroborate, 4-cyano-phenylglycine and N-methyl-morpholine in dimethylformamide.

Utilization: 37% of the theoretical,

Rf value: 0.47 (silica gel; ethyl acetate)

h. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert-butyloxy-carbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole

It was produced analogously to example 1f from 2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert-butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone and glacial acetic acid.

Utilization: 60% of the theoretical,

Rf value: 0.37 (silica gel; ethyl acetate)

i. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole

1.3 g (2.3 mmol) 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]- of benzimidazole is dissolved in 20 ml of dioxane and, after the addition of 40 ml of semiconc. hydrochloric acid, stir for two hours at room temperature. The solution is mixed with ice, basified with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.

Yield: 0.9 g (98% of theoretical),

Rf value: 0.14 (silica gel/ethyl acetate/ethanol = 9:1)

k. 2-(4-cyano-phenylamino-methyl)-1-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole

0.4 g of (1.04 ithunol) 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole is dissolved in 10 ml of ethanol and after the addition of 0.3 ml (2.7 mmol) of ethyl acrylate, stirred for 24 hours at 95°C. The solvent is distilled off and the residue is chromatographed on silica gel eluting with methylene chloride/ethanol (20:1 and 4:1).

Yield: 0.16 g (31% of theoretical),

Rf value: 0.26 (silica gel; ethyl acetate/ethanol = 9:1)

1. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-(2-ethoxy-carbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

2. - benzimidazole hydrochloride

It was produced analogously to example 1g from 2-(4-cyano-phenylamino-methyl)-1-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl) -ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 96% of the theoretical,

C28H37N7O3 x HCl (519.65/556.11)

mass spectrum: (M+H)* = 520

(M+Na)+ = 542

The following compounds were obtained analogously to example 6:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonylpropionylamino)-1-ethoxycarbonyl-ethyl]-benz-imidazole hydrochloride

Utilization: 69% of the theoretical,

C27H34N6O5 x HCl (522.62/555.08)

mass spectrum: (M+H)+ = 523

(M+H+Na)++ = 273

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonylmethylcarbonylamino)-1-(pyrrolidine-1-carbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 95% of the theoretical,

C28H35N7O4 x HC1 (533.64/570.10)

mass spectrum: (M+H)+ = 534

(M+Na)+ = 556

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonylpropionylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 20% of the theoretical,

C29H37N7O4 x HCl (547.66/584.12)

mass spectrum: (M+H)+ = 548

(M+H+Na)++ = 285.7

(4) 2-[4-amidinophenyl-N-(2-ethoxycarbonylethyl)-aminomethyl]-1-methyl-5-[1-dimethylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 91% of the theoretical,

C30H41N7O3 x HCl (547.71/584.17)

mass spectrum: (M+H)+ = 548

(M-H)- =546

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonylethylamino)-1-(dimethylaminocarbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 40% of the theoretical,

Rf value: 0.60 (RP 18 reverse phase; 5% NaCl/methanol solution = 1/1)

C26H35N7O3 x HCl (493.63/530.08)

mass spectrum: (M+H)+ = 494

(M-H+2HCl)- = 564/566/568 (Cl2)

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Rf value: 0.40 (silica gel; methylene chloride/methanol = 4:1 + 1% glacial acetic acid)

C27H35N7O3 x HCl (505.63/542.08)

mass spectrum: (M+H)+ = 506

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonylethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 85% of the theoretical,

Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1)

C27H37N7O3 x HCl (507.64/544.14)

mass spectrum: (M+H)+ = 508

(M+Cl)- = 542/4 (Cl)

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(methoxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole hydrochloride

Utilization: 99% of the theoretical,

Rf value: 0.21 (silica gel; methylene chloride/methanol = 4:1 + 1% glacial acetic acid)

C26H33N7O3 x HC1 (491.60/528.05)

mass spectrum: (M+H)+ = 492

(M-H+HCl)- = 526/8 (Cl)

(M-H+2HCl)- = 562/4/8 (Cl2)

(9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N,N-bis-(ethoxycarbonylmethyl)amino)-1-(pyrrolidinecarbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 65% of the theoretical,

Rf value: 0.35 (silica gel; methylene chloride/methanol = 4:1 -f 1% glacial acetic acid)

C31H41N7O5 x HCl (591.72/628.17)

mass spectrum: (M+H)+ = 592

(M-H+HCl)- = 626/8 (Cl)

(M-H+2HCl)- = 662/4/6 (Cl)2

(10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 9% of the theoretical,

Rf value: 0.50 (RP 8 reverse phase; methanol/5% NaCl solution =3:2)

C26H33N7O4 x HCl (507.60/544.05)

mass spectrum: (M+H)+ = 508

(11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonyl-ethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

(12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(N-methyl-N-ethylaminocarbonyl)-ethyl]

- benzimidazole dihydrochloride

Utilization: 58% of the theoretical,

Rf value: 0.70 (RP 8 reverse phase; methanol/5% NaCl solution = 3:2)

C26H35N7O3 x 2HCl (493.62/566.52)

mass spectrum: (M+H)+ =494

(M+HC1-H)- = 528/30 (Cl)

(13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-((N,N-di-(ethoxycarbonylmethyl)-amino)-1-(N-methyl-N

-ethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride

Utilization: 30% of the theoretical,

Rf value: 0.40 (RP 8 reverse phase; methanol/5% NaCl solution =3:2)

C30H41N7O5 x 2HC1 (579.71/652.62)

mass spectrum: (M+H) + = 580

(M-H)- = 578

(14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole dihydrochloride

Utilization: 82% of the theoretical,

Rf value: 0.60 (RP 8 reverse phase; methanol/5% NaCl solution = 3:2)

C28H37N7O3 x 2HCl (519.65/592.75)

mass spectrum: (M+H)+ = 520

(M-H+HCl)- = 534/6 (Cl)

(M-H+2HC1)- = 590/2/4 (Cl2)

(15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(diethylaminocarbonyl)-ethyl]

- benzimidazole dihydrochloride

Utilization: 88% of the theoretical,

Rf value: 0.60 (RP 8 reverse phase; methanol/5% NaCl solution = 3:2)

C27H37N7O3 x 2HC1 (507.64/580.56)

mass spectrum: (M+H) + = 508

(M-H+2HC1)- = 578/580/582 (C12)

(16) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethyl-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole dihydrochloride

Utilization: 46% of the theoretical,

Rf value: 0.43 (silica gel; methylene chloride/methanol=4:1 + 1% glacial acetic acid)

C28H37N7O3 x 2HCl (519.65/592.56)

mass spectrum: (M+H)+ = 520

(M+Cl)- = 554/6 (Cl)

(17) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole dihydrochloride

(18) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-ethoxy-carbonyl-propylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole dihydrochloride

Utilization: 95% of the theoretical,

Rf value: 0.50 (RP 8 reverse phase; methanol/5% solution

NaCl = 1:1)

C29H39N7O3 x 2HCl (533.68/606.58)

mass spectrum: (M+H)+ = 534

Example 7

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino]cyclopropyl] benzimidazole hydrochloride

a. 4-((1-tert.butyloxycarbonylamino)cyclopropyl)-2-nitro-N-methyl-aniline

15.0 g (63.5 irunol) 4-((1-carboxy)cyclopropyl)-2-nitro-N-methyl-aniline and 17.6 ml (127 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and at 0° 8.3 g (76 mmol) of ethyl chloroform was added to C. After one hour at room temperature, 0.75 g of tetrabutylammonium bromide is added. Then a solution of 6.3 g (96 mmol) of sodium azide in 20 ml of water is added drop by drop. After one hour at 0°C, the solution is diluted with water and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The residue is dissolved in 200 ml of tert.butanol and refluxed for two hours. The solvent is concentrated by evaporation, the residue is chromatographed on silica gel and washed with methylene chloride.

Yield: 15.5 g (77% of the theoretical,

Rf value: 0.83 (silica gel; methylene chloride/methanol = 9.5:0.5)

b. 4-((1-amino)cyclopropyl)-2-nitro-N-methyl-aniline-hydrochloride

15.5 g (0.05 mol) of 4-[(1-tert.butyloxy-carbonyl-amino)-cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 50 ml of ethanol and 50 ml of ethanolic hydrochloric acid and it is stirred for 7 hours at room temperature. The solvent is distilled off, the residue is triturated with ether, sucked off and dried.

Utilization: 98% of the theoretical,

Rf value: 0.44 (silica gel; methylene chloride/methanol = 9.5:0.5)

c. 4-[(1-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl-aniline

12.0 g (0.05 mol) of 4-[(1-amino)cyclopropyl]-2-nitro-N-methyl-aniline hydrochloride is dissolved in 500 ml of tetrahydrofuran and after the addition of 4.1 g (0, 05 mol) of cyclopentanone and 3.2 ml of glacial acetic acid, 13.6 g (0.064 mol) of sodium triacetoxyborohydride are added in portions under a nitrogen atmosphere. After 16 hours at room temperature, the mixture is diluted with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and washed with ethyl acetate/cyclohexane (1:1).

Yield: 10.8 g (80% of theoretical),

Rf value: 0.56 (silica gel; methylene chloride/methanol = 9.5:0.5)

d. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-nitro-N-methyl-aniline

1.0 g (3.6 mmol) of 4-[(1-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl-aniline is dissolved in 30 ml of tetrahydrofuran and after the addition of 0.45 g (4.4 mmol) of triethylamine , 0.65 g (4.4 mmol) of ethyl succinate chloride was added and the resulting mixture was stirred for 4 hours at room temperature. This is then diluted with ethyl acetate and sodium hydrogen carbonate solution, the organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1:1).

Yield: 1.3 g (90% of theoretical),

Rf value: 0.46 (silica gel; ethyl acetate/cyclohexane = 1:1)

e. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-amino-N-methyl-aniline

It was prepared analogously to example 1d from 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-nitro-N-methyl-aniline and palladium on activated carbon/hydrogen in methylene chloride/ethanol .

Rf value: 0.18 (silica gel; ethyl acetate/cyclohexane = 1:1)

f. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbons

1-amino-N-methyl-aniline

It was produced analogously to example 1c from 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N ,N,M',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenyl-glycine and triethylamine in dimethylformamide.

Utilization: 96% of the theoretical,

Rf value: 0.54 (silica gel; methylene chloride/methanol = 9.5:0.5)

g. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[N-cyclo-pentyl-N-(3-ethoxycarbonylpropionyl)-amino]-cyclopropyl]

- benzimidazole

It was produced analogously to example 1f from 4-[1-(N-{3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.

Utilization: 52% of the theoretical,

Rf value: 0.81 (silica gel; methylene chloride/methanol = 9:1)

h. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino]-cyclopropyl]-benzimidazole hydrochloride

It was produced analogously to example 1g from 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino]cyclopropyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol .

Utilization: 36% of the theoretical,

C30H38N6O3 x HCl (530.68/567.14)

mass spectrum: (M+H) + =531

Example 8

2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3-ethoxy-carbonylmethyl-imidazolin-2, 4-dion-5-yl)benzimidazol-

hydrochloride

a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonyl-methylaminocarbonylamino)-1-(pyrroyldin-1-yl)

-carbonyl)-ethyl]-benzimidazole

1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrroyldin-1-yl-carbonyl)-ethyl]-benzimidazole is dissolved in 10 ml of dimethylformamide and after the addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate, it is stirred for 45 minutes at room temperature. The solution is poured over ice water, the crystalline product is sucked off and dried. The residue is chromatographed on silica gel, eluting with methylene chloride/ethanol/ammonia (20:1:0.01 and 10:1:0.01).

Rf value: 0.77 (silica gel; methylene chloride/ethanol/ammonia = 9:1:0.01)

b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3-ethoxy-carbonylmethyl-imidazolin-2,4-dion-5-yl)-benzimidazole hydrochloride

It was produced analogously to example 1g from 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino-carbonylamino)-1-(pyrroyldin-1-yl-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Utilization: 68% of the theoretical,

C24H27N7O4 x HCl (477.52/513.99)

mass spectrum: (M+H)- = 478

Example 9

2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole hydrochloride

a. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylamino-methyl)-2-nitro-chlorobenzene

13.4 g (0.053 mol) of 4-chloro-3-nitro-benzyl bromide and 11.8 g (0.053 mol) of 2-tert.butyloxycarbonylethylamino-pyridine were mixed in 80 ml of N-ethyl-diisopropylamine for 3 hours at 90°C. The solution is concentrated by evaporation, the residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (8:2 and 7:3).

Yield: 8.2 g (40% of theoretical),

Rf value: 0.64 (silica gel; petroleum ether/ethyl acetate = 8:2)

b. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nitro-N-methyl-aniline

It was produced analogously to example 1b from a solution of 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nitro-chlorobenzene and methylamine. Utilization: 20% of the theoretical,

Rf value: 0.65 (silica gel; methylene chloride/ethanol = 9:1)

c. 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-amino-N-methyl-aniline

1.6 g (4 mmol) of 4-(2-tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2-nitro-N-methyl-aniline is dissolved in 200 ml of methanol and after the addition of 2 g of Raney nickel, it is mixed with s l ml of hydrazine hydrate. The solution was stirred for 30 minutes at room temperature and concentrated by evaporation. The residue is chromatographed on silica gel and washed with methylene chloride/ethanol (95:5).

Yield: 1.2 g (82% of theoretical),

Rf value: 0.33 (silica gel; methylene chloride/ethanol = 9:1)

d. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole-

hydrochloride

It was produced analogously to example 1c from 4-(2-tert.butyl-oxycarbonylethyl)-2-(pyridylaminomethyl)-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N' of ,N'-tetramethyl-uronium tetrafluoroborate, 4-cyano-phenylglycine in tetrahydrofuran and glacial acetic acid.

Utilization: 72% of the theoretical,

Rf value: 0.36 (silica gel; methylene chloride/ethanol = 9:1)

e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole-

hydrochloride

It is produced analogously to example Ig from 4-[(5-(2-tert-butyloxy-carbonylethyl)-2-pyridylaminomethyl-1-methyl-benz-imidazol-2-yl)-methylamino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 59% of the theoretical,

C27H31N7O2 x HCl (485.59/522.1)

mass spectrum: (M+H)+ = 486

The following compounds were obtained analogously to example 9: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(ethoxy-carbonylmethyl)-benzenesulfonylaminomethyl]-benzimidazole-hydrochloride

Utilization: 53% of the theoretical,

C27H30N6O4S x HCl (534.64/571.1)

mass spectrum: (M+H)+ = 535

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(N-methyl-phenyl-carbonylaminomethyl)]-benzimidazole hydrochloride

Utilization: 42% of the theoretical,

C25H26N6O x HC1 (426.53/462.96) mass spectrum: (M+H)+ = 427

Example 10

2-(4-amidinophenylamino-methyl)-1-methyl-5-[(2-methyl-benz-imidazol-1-yl)-methyl]-benzimidazole hydrochloride

a. 1-(4-chloro-3-nitrobenzyl)-2-methyl-benzimidazole

It is produced analogously to example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethyl sulfoxide.

Utilization: 78% of the theoretical,

C15H12ClN3O2 (301.7)

mass spectrum: M+ = 301/303

b. 1-(4-methylamino-3-nitrobenzyl)-2-methyl-benzimidazole

It is produced analogously to example 1b from 1-(4-chloro-3-nitrobenzyl)-2-methyl-benzimidazole and methylamine.

Utilization: 96% of the theoretical,

Rf value: 0.56 (silica gel; methylene chloride/ethanol = 19:1)

c. 1-(4-methylamino-3-aminobenzyl)-2-methyl-benzimidazole

It was prepared analogously to example Ic from 1-(4-methylamino-3-nitrobenzyl)-2-methyl-benzimidazole and hydrogen/Raney nickel. Utilization: 100% of the theoretical,

Rf value: 0.34 (silica gel; methylene chloride/ethanol = 19:1)

d. 2-(4-cyanophenylamino-methyl)-1-methyl-5-[(2-methyl-benz-imidazol-1-yl)methyl]-benzimidazole

A mixture of 1.94 g (11.0 mmol) of N-(4-cyanophenyl)-glycine and 1.78 g (11.0 mmol) of carbonyldimidazole was refluxed for 15 minutes in 80 ml of absolute tetrahydrofuran. After the addition of 2.7 g (10.46 mmol) of 1-(4-methylamino-3-amino-benzyl)-2-methyl-benzimidazole, the mixture was refluxed for a further 16 hours. The solution is then evaporated to dryness, the residue is mixed with 80 ml of glacial acetic acid and refluxed for 1 hour. This is then evaporated once to dryness, the resulting residue is mixed with 50 ml of water and made alkaline with conc. with ammonia (approx. pH 10). The crystallized product is filtered off, washed with a little water and dried. Yield: 4.1 g (96% of theoretical),

Rf value: 0.30 (silica gel; methylene chloride/ethanol = 19:1)

C25H22N6 (406.5)

mass spectrum: M+ = 406

e. 2-(4-amidinophenylamino-methyl)-1-methyl-5-[(2-methyl-benz-imidazol-1-yl)-methyl]-benzimidazole hydrochloride

I produce it analogously to example 1g from 2-(4-cyano-phenylamino-methyl)-1-methyl-5-[(2-methyl-benzimidazol-1-yl)-methyl]-benzimidazole and hydrochloric acid/ammonium carbonate.

Utilization: 59% of the theoretical,

C25H25N7 x HCl (423.5/459.9)

mass spectrum: (M+H)+ = 424

(M+2H)2+ = 217.7

The following compounds were obtained analogously to example 10:

(1) 2-(4-amidinophenyloxymethyl)-1-methyl-5-[(imidazol-1-yl)-methyl]-benzimidazole hydrochloride

Utilization: 30% of the theoretical,

C20H20N6O x HCl (360.4/396.9)

mass spectrum: (M+H)+ = 361

(M+2H)2+ = 181

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(imidazol-1-yl)-ethyl]-benzimidazole hydrochloride

Utilization: 70% of the theoretical,

C21H23N7 x HCl (373.46/410)

mass spectrum: (M+H)+ = 374

(M+2H)2+ = 187.6

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethyl-4-methyl-imidazol-1-yl)-ethyl]-benzimidazole-dihydrochloride

Utilization: 18% of the theoretical,

C24H29N7 x HCl (415.55/488.46)

mass spectrum: (M+H)+ = 416

(M+2H)2+ - 208.7

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-ethyl-4-methyl-imidazol-1-yl)-methyl]-benzimidazole-dihydrochloride

Utilization: 36% of the theoretical,

C23H27N7 x 2HCl (401.52/437.97)

mass spectrum: (M+H)+ = 402

(M+2H)2+ = 201.7

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(pyridin-2-yl)-N-methyl-aminomethyl]-benzimidazole-dihydrochloride

Utilization: 78% of the theoretical,

C23H25N7 x 2HCl (399.5/435.95)

mass spectrum: (M+H) + = 400

(M+2H)2+ = 200.6

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2-ethoxy-carbonyl-ethyl)-benzimidazol-1-yl)-methyl]-benzimidazole

-dihydrochloride

Utilization: 61% of the theoretical,

C29H31N7O2 x HCl (509.62/546.07)

mass spectrum: (M+H)+ = 510

(M+2H)2+ = 255.7

(M+H+Na)2+ = 266.7

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(imidazol-1-yl)-methyl]-benzimidazole hydrochloride

Utilization: 35% of the theoretical,

C20H21N7 x HCl (359.44/395.89)

mass spectrum: (M+H)+ = 360

(M+2H)2+ = 180.6

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2-acetyl-amino-ethyl)-4,5-dimethyl-imidazol-1-yl)-methyl]-benzimidazole

-dihydrochloride

Utilization: 42% of the theoretical,

mass spectrum: (M+H)+ = 473

(M+2H)2+ = 237

(M+H+Na)2+ = 248

(9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2-amino-carbonyl-ethyl)-4,5-dimethyl-imidazol-1-yl)-methyl]-benzimidazole

-dihydrochloride

Utilization: 68% of the theoretical,

C25H30N8O x 2HCl (458.6/531.51)

mass spectrum: (M+H)+ = 459

(M+2H)2+ = 230

(10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-methyl-4-ethoxycarbonyl-imidazol-1-yl)-methyl]-benzimidazole hydrochloride

Utilization: 34% of the theoretical,

C24H27N7O2 x HCl (445.53/481.98)

mass spectrum: (M+H)+ = 446

(M+2H)2+ = 223.5

(M+H+Na)2+ = 234.5

(11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(3-(3-ethoxy-carbonyl-n-propyl)-benzimidazol-2-on-1-yl)-methyl]

- benzimidazole hydrochloride

C30H33N7O3 x HCl (539.64/576.09)

mass spectrum: (M+H)+ = 540

(M+H+Na)2+ = 281.7

(12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(3-(2-ethoxy-carbonyl-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl)- methyl]

- benzimidazole hydrochloride

Utilization: 29% of the theoretical,

C28H30N8O3 x HCl (526.6/563.05)

mass spectrum: (M+H)+ = 527

(M+2H)2+ = 264

(M+H+Na)2+ = 275

(13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-phenyl-imidazol-1-yl)-methyl]-benzimidazole hydrochloride

Utilization: 58% of the theoretical,

C26H25N7 x HCl (435.54/472)

mass spectrum: (M+H)+ = 436

(M+Na) + = 218.6

(14) 2-(4-amidinophenylaminomethyl)-1-methyl-S-[(4,5-dimethyl-2-(2-ethoxycarbonylethyl)-imidazol-1-yl}-methyl]-benzimidazole

-dihydrochloride

Utilization: 52% of the theoretical,

C27H33N7O2 x HCl (487.61/560.52)

mass spectrum: (M+H) + = 488

(M+2H)24 = 244.6

Example 11

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride

a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(2-tert.butyl-oxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)

-ethyl]-benzimidazole

0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and 1.65 g (( 5.5 mmol) of tert.butyl 2,4-dibromobutyrate was dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmol) of sodium carbonate and stirred under nitrogen for 30 hours at 55° C. When cooled, the precipitate is filtered off and washed with ethanol. The filtrate is concentrated by evaporation, the residue is chromatographed on silica gel eluting with ethyl acetate and ethyl acetate/ethanol/ammonia (20:1:0.01). The desired fractions are combined and concentrated by evaporation. Utilization: 0.44 g (44% of theoretical) as a mixture of diastereomers,

C31H38N6O3 (542.69)

mass spectrum: (M+H)+ = 543

b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

Produced analogously to example 1g from 2-(4-cyanophenyl-amino-methyl-1-methyl-5-[1-(2-tert.butyloxy-carbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl- carbonyl)-ethyl]-benz-imidazole and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 12% of the theoretical,

C29H37N7O3 x HCl (531.66/568.12)

mass spectrum: (M+H) + = 532

(M+H+HC1)2+ = 568/70 (Cl)

Example 12

(E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl] benzimidazole hydrochloride

a. (E/Z)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]-cyclopropyl]

- benzimidazole hydrochloride

897 mg (4.0 mmol) of triethyl phosphonoacetate were dissolved in 30 ml of tetrahydrofuran under argon. At -15°C, 449 mg (4.0 mmol) of potassium tert.butoxide is added. After 30 minutes, 815 mg (2.0 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyridin-3-yl-carbonyl)cyclopropyl]-benzimidazole were added gradually and the mixture was stirred overnight at room temperature. The solution is then refluxed for a further 6 hours and concentrated by evaporation. The residue was mixed with sodium chloride solution and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in dichloromethane and chromatographed on silica gel, eluting with dichloromethane containing 5% ethanol. The desired fractions are concentrated by evaporation, the residue is triturated with ether, evaporated and dried.

Yield: 365 mg (38% of theoretical),

b. ((E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]-cyclopropyl]-benzimidazole hydrochloride

It was produced analogously to example 1g from (E/Z)-2-(4-cyanophenyl-aminomethyl)-1-methyl-5-[1-[(pyridin-3-yl)-ethoxycarbonylmethylidene)-methylene]cyclopropyl]-benzimidazole and of hydrochloric acid/ammonium carbonate in ethanol. Utilization: 58% of the theoretical,

C29H30N6O2 x HCl (494.60/531.05)

mass spectrum: (M+H)+ = 495

The following compound was obtained analogously to the example

12: (1) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-ethoxycarbonylmethylidene)methylene]-cyclopropyl]

- benzimidazole hydrochloride

Utilization: 72% of the theoretical,

C29H30N6O2 x HCl (494.60/531.05)

mass spectrum: (M+H)+ = 495

Example 13

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride

200 mg (0.35 mmol) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl ]-benzimidazole hydrochloride is dissolved in 30 ml of 6M hydrochloric acid and stirred for 13 hours at room temperature. The reaction mixture is concentrated by evaporation with the addition of toluene, the residue is triturated with acetone/ether, suction, washed with ether and dried.

Yield: 200 mg (>100% of the theoretical, contains ammonium chloride),

C27H33N7O3 x HCl (503.62/540.07)

mass spectrum: (M+H) + = 504

The following compounds were obtained analogously to example 13:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimidazole hydrochloride

Utilization: 91% of the theoretical,

Rf value: 0.75 (reverse phase; 5% solution

NaCl/methanol =1:1)

C24H31N7O3 x HCl (465.56/502.01)

mass spectrum: (M+H)+ = 466

(M-H+2HC1)' = 537/539 (C12)

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole dihydrochloride

Utilization: 70% of the theoretical,

Rf value: 0.51 (reverse phase; 5% NaCl/methanol solution = 3:2)

C25H31N7O3X 2 HCl (477.57/550.48)

mass spectrum: (M+H)+ = 478

(3) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-carboxymethylidene)-methylene]-cyclopropyl]

- benzimidazole hydrochloride

Utilization: 65% of the theoretical,

C27H26N7O3 x HCl (466.55/503.0)

mass spectrum: (M+H)+ =467

(M+C1)+ = 501/503 (Cl)

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole dihydrochloride

Utilization: 99% of the theoretical,

Rf value: 0.55 (reverse phase RP 8; methanol/5% NaCl solution = 1:1)

C28H35N7O4 x 2HCl (533.64/606.64)

mass spectrum: (M+H) + = 534

(M-H)- = 532

(M-H+HCl) = 568/70 (Cl)

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)-ethyl]

- benzimidazole dihydrochloride

Utilization: 75% of the theoretical,

Rf value: 0.54 (reverse phase RP 8; methanol/5% NaCl solution = 1:1)

C25H33N7O3 x 2HCl (479.59/552.59)

mass spectrum: (M+H)+ = 480

Example 14

2-[4-(N-hexyloxycarbonylamidino)-phenylaminomethyl-1-methyl-5-(1-(2-ethoxycarbonylethylamino)-1-(dimethylamino

-carbonyl)-ethyl]-benzimidazole-dihydrochloride

1.5 g (2.8 mmol) of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxycarbonylethylamino)-1-(dimethylaminocarbonyl)-ethyl]-benzimidazole hydrochloride is dissolved in 14 ml of water and 55 ml of tetrahydrofuran, mixed with 2.0 g of potassium carbonate and 1.0 ml (6 mmol) of hexyl chloroformate and stirred for 4 hours at room temperature. The residue after removing the solvent in vacuo is mixed with NaCl solution and extracted 3 times with methylene chloride. The combined organic phases are washed with a little water, dried over magnesium sulfate and concentrated by evaporation. The crude product was purified on silica gel by washing with methylene chloride and 2 to 7.5% ethanol. The pure fractions are combined, concentrated by evaporation, dissolved in a little ethyl acetate and mixed with petroleum ether. The solid substance is sucked off, washed with petroleum ether and dried.

Yield: 0.8 g (43% of theoretical),

C33H47N7O5 (621.79)

Rf value: 0.50 (silica gel; methylene chloride/ethanol = 19:1)

mass spectrum: (M+H)+ = 622

(M+Na)+ = 644

Example 15

2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride

a. Methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate

35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) was added dropwise to a solution of 8.1 ml of diisopropylamine (85 mmol) in 20 ml of tetrahydrofuran at -78°C. Then, a solution of 10.0 g (50 mmol) of methyl 2-(4-chloro-phenyl)-propionate in 30 ml of tetrahydrofuran was added drop by drop at -78°C. Then, gaseous formaldehyde is introduced into the reaction mixture at -20°C for 20 minutes. After adding 5% citric acid and glacial acetic acid, the mixture is extracted with ethyl acetate. The organic phases are washed with 1N sulfuric acid, water, saturated sodium bicarbonate solution and NaCl solution, and dried over magnesium sulfate. The crude product was purified on silica gel eluting with cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1 and 0:1). Pure fractions are combined and concentrated by evaporation.

Yield: 9.7 g (84% of theory) of yellow oil,

Rf value: 0.25 (silica gel; petroleum ether/ethyl acetate = 4:1)

b. 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid

It was produced analogously to example 4 from a solution of methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxide in ethanol.

Utilization: 83% of the theoretical,

Rf value: 0.55 (silica gel; ethyl acetate/cyclohexane = 2:1 + glacial acetic acid)

c. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-nitroxy-propionic acid

It is produced analogously to example 1a from 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid.

Utilization: 90% of the theoretical,

melting point: 129-132°C

C10H9ClN2O7 (304.64)

d. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-hydroxy-propionic acid

It is produced analogously to example 6 from 2-(4-chloro-3-nitro-phenyl)-3-nitro-oxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane.

Utilization: 98% of the theoretical,

C10H10ClNO5 (259.65)

mass spectrum: (M-H)- = 258/60 (Cl)

(2M-H)- = 517/9 (Cl2)

e. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-propionic acid

It is produced analogously to example 1b from 2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.

Utilization: 81% of the theoretical,

C18H20ClN2O5 (344.37)

mass spectrum: M+ = 344

f. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one

It is produced analogously to example Ic from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.

Utilization: 96% of the theoretical,

C22H27N3O4 (397.48)

mass spectrum: M+ = 398

(M+Na)+ = 420

g. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulfonyloxy-1-pyrrolidin-1-yl-propan-1-one

A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1- it in 20 ml of tetrahydrofuran is mixed at room temperature with 1.3 ml (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 ramoles) of methanesulfonyl chloride is added drop by drop at 2-5°C. After 2 hours at room temperature, the resulting precipitate is suctioned off and the filtrate is concentrated by evaporation. The crude product reacts further without further purification.

Yield: 1.4 g (98% of theoretical)

h. 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one

A solution of 1.4 g (2.9 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulfonyloxy-1-pyrrolidin-1-yl-propane- 1-one in 10 ml of dimethyl formamide is mixed with 20 ml of a 40% aqueous solution of methylamine and heated for 70 minutes at 100°C. When cooled, the reaction mixture was mixed with ice water and extracted with ethyl acetate. The organic phases are washed with water and NaCl solution, dried over magnesium sulfate and concentrated by evaporation. The crude product was purified on silica gel by washing with ethyl acetate/ethanol (10:1, 9:1, 4:1 + 1% conc. ammonia). Pure fractions are combined and concentrated by evaporation.

Utilization: 740 mg (61% of theoretical),

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1 + 1% conc. ammonia)

i. 2-[4-(benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one

It was produced analogously to example 7d from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one and methyl malonate chloride.

Utilization: 84% of the theoretical,

Rf value: 0.65 (silica gel; ethyl acetate/ethanol = 9:1 + ammonia)

C27H34N4O6 (510.60)

mass spectrum: (M-H)- = 509

(M+Na) + = 533

j. 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N-methoxy-carbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl

-propan-1-one

It was produced analogously to example 1d from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonyl-methyl-carbonyl-methylamino)-1-pyrrolidine-1- yl-propan-1-one and hydrogen/palladium on activated carbon.

Utilization: 100% of the theoretical,

Rf value: 0.40 (silica gel; ethyl acetate/ethanol = 9:1 + 1% conc. ammonia)

C20H30N4O4 (390.49)

mass spectrum: M+ = 390

k. 4-[2-(3-(N-Methoxycarbonylmethylcarbonyl-methylamino))-2-methyl-1-pyrrolidin-1-yl-propan-1-on-2-yl]-2-(4-cyano-phenyl)- aminomethylcarbonylamino-M-methyl-aniline

It is produced analogously to example le from 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and O- (benzo-triazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.

Utilization: 95% of the theoretical,

Rf value: 0.35 (silica gel; ethyl acetate/ethanol =9:1 +1% ammonia conc.)

l. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(pyrrolidino-carbonyl)-prop-2-yl]-benzimidazole

It was produced analogously to example 1f from 4-[2-(3-(N-methoxycarbonylmethylcarbonyl-methylamino))-2-methyl-1-pyrrolidin-1-yl-propan-1-on-2-yl]-2-(4 -cyanophenyl)-amino-methylcarbonylamino-N-methyl-aniline in glacial acetic acid.

Utilization: 47% of the theoretical,

Rf value: 0.20 (silica gel; ethyl acetate/ethanol = 9:1)

C29H34N6O3 (530.63)

mass spectrum: (M+H)+ = 531

(M+Na)+ = 553

m. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(pyrrolidino

-carbonyl)-prop-2-yl]-benzimidazole hydrochloride

It is produced analogously to example Ig from 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethyl-carbonyl-methyl-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole and of hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 65% of the theoretical,

Rf value: 0.30 (silica gel; methylene chloride/methanol = 4:1 + glacial acetic acid)

C30H39N7O4 x HCl (561.69/598.19)

mass spectrum: (M+H)+ = 562

(M+CIT = 596/8 (Cl)

The following compounds were obtained analogously to example 15.

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methoxy-carbonylmethyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride

Utilization: 89% of the theoretical,

Rf value: 0.35 (reverse phase RP 8; methanol/5% NaCl solution = 3:2)

C28H37N7O3 x HCl (519.66/556.11)

mass spectrum: (M+H) + = 520

(M-H+HCl)- = 554/6 (Cl)

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonylamino)-2-(pyrrolidinocarbonyl)-2-yl]

- benzimidazole-acetate

Utilization: 45% of the theoretical,

Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1% ethyl acetate)

C29H37N7O4 x CH3COOH (547.66/607.71)

mass spectrum: (M+H)+ = 548

(M-H)- = 546

(M-H+CH3COOH)- = 606

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(N-methylethylamino)

-carbonyl)-prop-2-yl]-benzimidazole hydrochloride

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethyl-methylamino)-2-(N-methyl-N-ethylamino-carbonyl)

-prop-2-yl]-benzimidazole hydrochloride

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylcarbonyl-methylamino)-2-(piperidino-carbonyl)

-prop-2-yl]-benzimidazole hydrochloride

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxy-carbonylmethylsulfonyl-methylamino)-2-(piperidino-carbonyl)

-prop-2-yl]-benzimidazole hydrochloride

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methoxy-carbonylmethylcarbonyl-methylamino)-2-(pyrrolidino-carbonyl)

-prop-2-yl]-benzimidazole-acetate

Utilization: 72% of the theoretical,

Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1% glacial acetic acid)

C29H37N7O4 CH3COOH (547.66/607.71)

mass spectrum: (M+H)+ = 548

(M-H)- = 546

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethoxy-carbonyl-ethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

(9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylsulfonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

Utilization: 14% of the theoretical,

Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2)

C28H37N7O5S x HCl (583.65/620.17)

mass spectrum: (M+H)+ = 584

(M+Ma)+ = 606

(10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl)-methylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2

-yl]-benzimidazole hydrochloride

(11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole dihydrochloride

Utilization: 40% of the theoretical,

C28H37N7O3 x 2HCl (519.65/592.56)

mass spectrum: (M+H)+ = 520

(M+Na)+ = 542

(M+HCOO) = 564

(M+C1)- = 554

Example 16

2-(4-amidinophenylaminoethyl)-1-methyl-5-[1-(carboxymethyl-amino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride

It is produced by hydrolysis of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride with sodium hydroxide solution in ethanol.

Utilization: 90% of the theoretical,

Rf value: 0.65 (reverse phase RP 8; methanol/5% NaCl solution = 3:2)

C24H29N7O4 x HCl (479.54/515.99)

mass spectrum: (M+H)- = 480

The following compounds were produced analogously to example 16:

(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl]

- benzimidazole hydrochloride

(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(N-methyl-N-ethylaminocarbonyl)-ethyl]

- benzimidazole hydrochloride

Utilization: 93% of the theoretical,

Rf value: 0.40 (reverse phase RP 8; methanol/5%-tna

NaCl solution = 1:1)

C24H31N7O3 x HCl (465.57/502.02)

mass spectrum: (M+H)+ =466

(M+C1-H)- = 500/2 (Cl)

(3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole dihydrochloride

Utilization: 89% of the theoretical,

Rf value: 0.57 (reverse phase RP 8; methanol/5%-tna

NaCl solution = 4:3)

C27H35N7O3 x 2HCl (505.63/578.54)

mass spectrum: (M+H)+ = 506

(M+2H)++ = 253

(M+H+Na)++ = 264.5

(4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

Utilization: 90% of the theoretical,

Rf value: 0.55 (reverse phase RP 8; methanol/5% NaCl solution = 4:6)

C27H33N7O4 x HCl (519.61/556.06)

mass spectrum: (M+H) + = 520

(M-H)- = 518

(5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)-prop-2

-yl]-benzimidazole hydrochloride

(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methylcarbonyl-methylamino)-2-(N-ethyl-methylaminocarbonyl)

-prop-2-yl]-benzimidazole hydrochloride

(7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methylcarbonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

(8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methylsulfonyl-methylamino)-2-(piperidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

(9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(piperidinocarbonyl)-ethyl]-benzimidazole

-hydrochloride

Utilization: 81% of the theoretical,

Rf value: 0.40 (reverse phase RP 8; methanol/5% NaCl solution = 1:1)

C26H33N7O3 (491.60/528.05)

mass spectrum: (M+H)+ = 492

(M-H)- = 490

(10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

(11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylsulfonylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]

- benzimidazole hydrochloride

(12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(diethylaminocarbonyl)-ethyl]-benzimidazole

-hydrochloride

Utilization: 70% of the theoretical,

Rf value: 0.50 (reverse phase RP 8; methanol/5% NaCl solution = 1:1)

C25H33N7O3 x HCl (479.59/516.05)

mass spectrum: (M+H) + = 480

(M-H)- = 478

(M-H+HCl)- = 514/516 (Cl)

(13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

-dihydrochloride

Utilization: 22% of the theoretical,

Rf value: 0.50 (reverse phase RP8; 5% NaCl/methanol solution = 1:1)

C26H33N7O3 x 2HCl (491.60/564.51)

mass spectrum: (M+H)+ = 492

(M-H)- = 490

(14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxy-methyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]

-benzimidazole -dihydrochloride

Rf value: 0.48 (reverse phase RP8; 5% solution NaCl/methanol =3:2)

C26H33N7O3 x 2HCl (491.60/564.51)

mass spectrum: (M+H) + = 492

(M-H)- = 490

(15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3-carboxy-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

-dihydrochloride Yield: 82% of the theoretical,

Rf value: 0.73; (reverse phase; 5% NaCl/methanol solution = 1:1)

C27H35N7O3 x 2HCl (505.63/578.54) mass spectrum: (M+H) + = 506

Example 17

2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

A suspension of 1.4 g (2.4 mmol) of 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride in 5 ml of N- of ethyl diisopropylamine and 2 ml of dimethylformamide is mixed with 1.5 g (6 mmol) of 4-nitrophenyl benzoate, and heated until a clear solution is obtained. After 2 hours at 120°C, the solution is concentrated by evaporation in a vacuum, when it cools, the residue is dissolved in dichloromethane and purified on silica gel, washing first with dichloromethane and then with dichloromethane/ethanol (50:1, 25:1, 18:1 ). The pure fractions are combined, concentrated by evaporation, triturated with water, sucked off and dried.

Yield: 0.7 g (49% of theoretical),

Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1)

C34H39N7O4 (609.73)

mass spectrum: (M+H)+ = 610

(M+Na)+ = 632

(M-H)- = 608

The following compounds were obtained analogously to examples 14 and 17:

(1) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)-ethyl]-benzimidazole

Utilization: 53% of the theoretical,

Rf value: 0.35 (silica gel; methylene chloride/ethanol =

9:1)

C34H47N7O5 (633.79)

mass spectrum: (M+Na)+ = 656

(M-H)- = 632

(2) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)-ethyl]-benzimidazole

Utilization: 46% of the theoretical,

Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1)

C36H51N7O5 (661.84)

mass spectrum: (M+Na)+ = 684

(M-H)- = 660

(3) 2-[4-(N-n-hexyloxycarbonyl-amidino)-phenylaminomethyl)-1-methyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)-ethyl]-benzimidazole

(4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl)-3-1-methyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)ethyl]-benzimidazole

Utilization: 32% of the theoretical,

Rf value: 0.27 (silica gel; methylene chloride/ethanol = 9:1)

C35H49N7O5 (647.82)

mass spectrum: (M+Na)+ = 670

(M-H)- = 646

(5) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methyl-amino)

-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 52% of the theoretical,

Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1)

C37H51N7O6 (689.85)

mass spectrum: (M+H)+ = 690

(M-H)- = 688)

(M+Na)+ = 712

(M+HCl-H)- = 724/26 (Cl)

(6) 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methyl-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl] - benzimidazole

(7) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methyl)

-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

Utilization: 21% of the theoretical,

Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1)

C36H49N7O6 (675.83)

mass spectrum: (M+H)+ = 676

(M+Na)+ = 698

(M+HC1-H)- = 724/26 (Cl)

(8) 2-[4-(N-n-octyloxycarbonyl-amidino)-phenylaminomethyl)-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methyl-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl] - benzimidazole

(9) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 34% of the theoretical,

Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1 + 1% ammonia)

C33H37N7O4 (595.70) mass spectrum: (M-H)- = 594

(M+Na) + = 618

(10) 2-[4-(N-isopropyloxycarbonylamidino)-phenylamino-methyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methyl-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl] - benzimidazole

Utilization: 66% of the theoretical,

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)

C34H45N7O6 (647.77)

mass spectrum: (M+H) + = 648

(M-H)+ = 646

(M+Na)+ =670

(11) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2

-(pyrrolidinocarbonyl)~prop-2-yl]-benzimidazole Yield: 23% of the theoretical,

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)

C37H43N7O5 (665.79)

mass spectrum: (M+H)+ = 666

(M-H)+ = 664

(M+Na)+ = 688

(M+H+Cl)+ = 700/2 (Cl)

(12) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methyl-amino)-2

-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

Utilization: 67% of the theoretical,

Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1)

C36H41N7O5 (651.76)

mass spectrum: (M+H)+ = 652

(M-H)- = 650

(M+Na)+ =674

(13) 2-[4-(N-n-butyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methyl)

-amino)-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 45% of the theoretical,

Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1)

C34H45N7O6 (647.77)

mass spectrum: (M+H) + = 648

(M-H) + = 646

(M+Na) + = 670

(M-H+HC)- = 682/4 (Cl)

(14) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-2

-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

Utilization: 54% of the theoretical,

Rf value: 0.40 (silica gel; methylene chloride/ethanol = 9:1)

C33H43N7O6 (633.75)

mass spectrum: (M+H)+ = 634

(M-H)- = 632

(M+Na)+ = 656

(15) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl-1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl-methyl-amino)-2

-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

Utilization: 53% of the theoretical,

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)

C32H41N7O6 (619.72)

mass spectrum: (M+H)+ = 620

(M-H)- = 618

(M+Na)+ = 642

(16) 2-[4-(N-pyridin-3-yl-carbonylamidino)-phenylamino-methyl]-1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino)

-2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole

Utilization: 16% of the theoretical,

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)

C36H42N8O5 (666.78)

mass spectrum: (M-H)- = 665

(M+Na) + = 689

(17) 2-[4-(N-n-butyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 52% of the theoretical,

Rf value: 0.42 (silica gel; methylene chloride/ethanol = 9:1)

C32H43N7O5 (605.74)

mass spectrum: (M+H)+ = 606

(M+Na)+ = 628

(M-H)- = 604

(18) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)

-ethyl]-benzimidazole

Utilization: 30% of the theoretical,

Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1)

C32H39N7O5 (577.68)

mass spectrum: (M+H)+ = 578

(M+Na)+ = 600

(M-H)- = 576

(19) 2-[4-(N-benzyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)-ethyl]-benzimidazole

Utilization: 51% of the theoretical,

Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1)

C35H41N7O5 (639.75)

mass spectrum: (M+Na) + = 662

(M-H)- = 638

(20) 2-[4-(N-pyridin-3-yl-carbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 84% of the theoretical,

Rf value: 0.20 (silica gel; ethyl acetate/ethanol = 4:1)

C33H38N8O4 (610.72)

mass spectrum: (M+H)+ = 611

(M-H)- = 609

(M-HCOO)- =611

(21) 2-[4-(N-acetoxymethyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1

-(pyrrolidino-carbonyl)-ethyl]-benzimidazole

Utilization: 42% of the theoretical,

Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1)

C31H39N7O5 (621.09)

mass spectrum: (M+Na)+ = 644

(M-H)- = 620

(22) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)-phenyl-aminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 73% of the theoretical,

Rf value: 0.54 (silica gel; methylene chloride/ethanol = 9:1)

C30H36Cl3N7O5 (681)

mass spectrum: M+ = 679/81/3 (Cl3)

(M+Na) + = 702/4/6 (Cl3)

(M-H)- = 678/80/2 (Cl3)

Example 18

2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

A solution of 0.2 g (0.3 mmol) of 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimide -azole in 3 ml of tetrahydrofuran and 2.5 ml of ethanol is mixed with 1.1 ml of 1N sodium hydroxide solution and stirred for 4 hours at room temperature. The reaction mixture is concentrated by evaporation and mixed with 1 ml of 1N hydrochloric acid. After 12 hours at room temperature (pH 4), 2 drops of ammonia (33%) are added, after which an abundant yellow precipitate forms. The resulting precipitate is suctioned off, the filtrate is mixed with 1 ml of 1N hydrochloric acid and concentrated by evaporation with the addition of toluene. The residue is triturated with acetone, filtered off, washed with diethyl ether and dried.

Yield: 0.1 g (50% of theoretical),

Rf value: 0.35 (severse phase RP 8; methanol/5% NaCl solution = 2:1)

C34H47N7O5 (633.79)

mass spectrum: (M+H)+ = 634

(M+H+Na) + = 328.5

Example 19

2-[4-(N-hydroxyamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

A suspension of 0.6 g (1.2 mmol) of 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 50 ml of ethanol was mixed with 0.47 g (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g (3.5 mmol) of sodium carbonate and refluxed for 17 hours. When it cools down, the residue is filtered off, the filtrate is concentrated by evaporation and taken up in water. It is extracted twice with dichloromethane, the combined organic phases are dried and concentrated by evaporation. The crude product was purified on silica gel, eluting with dichloromethane/ethanol (19/1 and 7/1). The pure fractions are combined, concentrated by evaporation, triturated with diisopropylether and dried.

Yield: 0.025 g (4% of theoretical),

Rf value: 0.68 (silica gel; methylene chloride/ethanol = 4:1)

C27H35N7O4 (521.62)

mass spectrum: (M-H)- = 520

(M+Na)+ = 544

Example 20

2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-pyrrolidinocarbonyl)-ethyl]-benzimidazole

a. Ethyl 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-acetate

It was produced analogously to example 9a from 4-(5-methyl-1,2,4-oxa-diazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine.

Utilization: 78% of the theoretical,

Rf value: 0.60 (silica gel; ethyl acetate/petroleum ether = 1:1)

b. 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-acetic acid It is produced analogously to example 4 from ethyl 4-(5-methyl-1,2,4-oxadiazol-3- yl)-phenylamino-acetate and sodium hydroxide solution in ethanol.

Utilization: 75% of the theoretical,

Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9:1)

c. 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-(pyrrolidin-1-yl-carbonyl)-ethyl]-

benzimidazole

It is produced analogously to example le/f from 2-(4-methyl-amino-3-amino-phenyl)-2-ter.butyloxycarbonyl-amino-1-pyrrolidin-1-yl-propanone, 4-(5-methyl-l ,2,4-oxadiazol-3-yl)-phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran followed by treatment with glacial acetic acid.

Utilization: 34% of the theoretical,

Rf value: 0.10 (silica gel; methylene chloride/ethanol = 9:1)

d. 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxy-carbonylmethylamino)-1-

(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Produced analogously to example 11 from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl] -benzimidazole, isopropyl bromoacetate and potassium carbonate in isopropanol/methylene chloride.

Utilization: 42% of the theoretical,

Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1)

e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopropyl-oxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-

benzimidazole-acetate

Produced analogously to example 1d from 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl) )-ethyl]-benzimidazole and hydrogen/palladium (10% on activated carbon) in ethanol/glacial acetic acid.

Utilization: 69% of the theoretical,

Rf value: 0.30 (silica gel; methylene chloride/ethanol = 7:3)

f. 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

It was produced analogously to example 17 from 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopropyloxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benz-imidazole-acetate and 4-nitrophenyl benzoate in N -ethyl-diisopropylamine/dimethylformamide.

Utilization: 26% of the theoretical,

Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1)

C35H41N7O4 (623.75)

mass spectrum: (M+Na)+ =646

(M-H)- = 622

The following compounds were produced analogously to example 20:

(1) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)

-ethyl]-benzimidazole

(2) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-phenylethyloxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(3) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 40% of the theoretical,

Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)

C35H49N7O5 (647, 82)

mass spectrum: (M+H) + - 648

(M-H)- - 646

(M+Na) + = 670

(4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1

-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 31% of the theoretical,

Rf value: 0.48 (silica gel; methylene chloride/ethanol = 9:1)

C37H53N7O5 (675.88)

mass spectrum: (M+H)+ = 674

(M+Na) + = 698

(5) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonyl-methylamino)

-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Utilization: 43% of the theoretical,

Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1)

C31H38Cl3N7O5 (695.05)

mass spectrum: (M-H)- = 692/694/696/698 (Cl3)

(6) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-pyrrolidino

-carbonyl)-ethyl]-benzimidazole Yield: 79% of the theoretical,

Rf value: 0.35 (silica gel; ethyl acetate/ethanol = 9:1)

C35H41N7O4 (623.76)

mass spectrum: (M+H)+ = 624

(M-H)- = 622 (M+HCOO)- = 668

(7) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidino

-carbonyl)-ethyl]-benzimidazole

Utilization: 53% of the theoretical,

Rf value: 0.39 (silica gel; ethyl acetate/ethanol = 9:1)

C37H53N7O5 (675.88)

mass spectrum: (M+H)+ = 676

(M+Na)+ = 698

(M-H)- = 674

Example 21

(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole hydrochloride

a. Ethyl 2-amino-2-(4-chloro-3-nitro-phenyl)-propionate

A mixture of 28 g (0.11 mol) of 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid in 200 ml of 5.6 N ethanolic hydrochloric acid is refluxed for 36 hours. The residue after evaporation of the solvent is suspended in 300 ml of ethyl acetate and mixed with 300 ml of saturated sodium hydrogen carbonate solution. The organic phase is washed twice with saturated sodium hydrogen carbonate solution and once with water. The obtained organic phase is dried over sodium sulfate and evaporated.

Yield: 21.1 g (68% of theory) light brown oil.

b. Ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionate

17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3-nitro-phenyl)-propionate were dissolved in 247 ml of isopropanol and 207 ml of methanol and mixed with 9.54 g (63 .6 mmol) of L-(+)-tartaric acid. The reaction mixture is heated to 100°C, resulting in a clear solution. The solution is cooled for 3 hours to 27°C and the precipitate obtained is suctioned off, washed with ethanol and dried. The resulting precipitate (21.5 g) is suspended in 400 ml of ethyl acetate and mixed with 400 ml of saturated sodium hydrogen carbonate solution. After extraction and phase separation, the organic phase is washed with water, dried and evaporated.

Yield: 7.68 g (44.4% of theory) light yellow oil,

[α]20 - + 4.38° (ethyl acetate)

HPLC analysis: ee value >98.6%,

c. (R)-(-)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid

It was produced analogously to example 4 from ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionate and a solution of sodium hydroxide in tetrahydrofuran.

Utilization: 63% of the theoretical,

[α]20 = -59.6° (methanol/water = 1:1).

d. (R)-2-tert.butyloxy-carbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid

It was produced analogously to example 5d from (R)-(-)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid and di-tert-butyl pyrocarbonate and triethylamine in dioxane.

Utilization: 100% of theoretical.

e. (R)-2-tert.butyloxy-carbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionic acid

It was produced analogously to example 1b from (R)-2-tert.butyloxy-carbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid and methylamine.

Utilization: 69% of the theoretical.

f. (R)-2-(4-methylamino-3-nitro-phenyl)-2-tert-butyloxy-carbonylamino-1-pyrrolidino-propanone

It is produced analogously to example Ic from (R)-2-tert-butyloxy-carbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionic acid, pyrrolidine and carbonyl diimidazole in tetrahydrofuran.

Utilization: 96% of the theoretical.

Mr. (R)-2-(4-methylamino-3-amino-phenyl)-2-tert-butyloxy-carbonylamino-1-pyrrolidino-propanone

It was prepared analogously to example Ic from (R)-2-(4-methyl-amino-3-nitro-phenyl)-2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone and hydrogen/palladium on charcoal in methanol.

Utilization: 99% of theoretical.

h. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert-butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]

- benzimidazole

It was produced analogously to example 1e/1f from (R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone, 4-cyanophenylglycine, carbonyl di-imidazole in tetrahydrofuran and then by cyclization in glacial acetic acid.

Utilization: 100% of theoretical.

i. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

It was produced analogously to example 6i from (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert-butyloxy-carbonyl-amino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and 6N hydrochloric acid in dioxane.

Utilization: 76% of the theoretical.

k. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]

- benzimidazole

It was prepared analogously to example 6k from (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and ethyl iodoacetate/potassium carbonate in acetone.

Utilization: 75% of the theoretical.

l. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxy-carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]

- benzimidazole hydrochloride

It was produced analogously to example 1g from (R)-2-(4-cyanophenylaminemethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.

Utilization: 95% of the theoretical.

m. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]

- benzimidazole hydrochloride

It was produced analogously to example 4 from (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and a solution of sodium hydroxide in ethanol.

Utilization: 100% of the theoretical,

C25H31N7O3 x 2HCl (477.57/550.5)

mass spectrum: (M+H)+ =478

(M-H+HCl)- = 512/514 (Cl)

(M-H+2HC1)- = 448/550/552 (Cl2)

Example 22

Dry ampoules containing 75 mg of active tar in 10 ml

Composition:

active substance 75.0 mg

mannitol 50.0 mg

water for injections ad 10.0 ml

Preparation:

The active substance and mannitol dissolve in water. After packaging, the solution is freeze-dried. To obtain a ready-to-use solution, the product is dissolved in water for injections.

Example 23

Dry ampoules containing 35 mg of active tar in 2 ml

Composition:

active substance 35.0 mg

mannitol 100.0 mg

water for injections ad 2.0 ml

Preparation:

The active substance and mannitol dissolve in water. After packaging, the solution is freeze-dried. To obtain a ready-to-use solution, the product is dissolved in water for injections.

Example 24

Tablet containing 50 mg of active substance

Composition

(1) active substance 50.0 mg

(2) lactose 98.0 mg

(3) corn starch 50.0 mg

(4) polyvinylpyrrolidone 15.0 mg

(5) magnesium stearate 2.0 mg

215.0 mg

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of substance (4). (5) is added to the dry granulate. Tablets are pressed from this mixture, flat and hemmed on both sides, and divided with a notch on one side. Tablet diameter: 9 mm.

Example 25

Tablet containing 350 mg of active substance

Composition

(1) active substance 350.0 mg

(2) lactose 136.0 mg

(3) corn starch 80.0 mg

(4) polyvinylpyrrolidone 30.0 mg

(5) magnesium stearate 4.0 mg

600.0 mg

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of substance (4). (5) is added to the dry granulate. Tablets are pressed from this mixture, flat and hemmed on both sides, and divided with a notch on one side. Tablet diameter: 12 mm.

Example 26

Capsules containing 50 mg of active substance

Composition

(1) active substance 50.0 mg

(2) dry corn starch 58.0 mg

(3) powdered lactose 50.0 mg

(4) magnesium stearate 2.0 mg

160.0 mg

Preparation:

(1) is triturated with (3). This is added to the mixture of substances (2) and (4) with vigorous stirring.

The powder mixture is packed into size 3 hard gelatin capsules on a capsule filling machine.

Example 27

Capsules containing 350 mg of active substance

Composition

(1) active substance 350.0 mg

(2) dry corn starch 46.0 mg

(3) powdered lactose 30.0 mg

(4) magnesium stearate 4.0 mg

430.0 mg

Preparation:

(1) is triturated with (3). This is added to the mixture of substances (2) and (4) with vigorous stirring.

The powder mixture is packed into O size hard gelatin capsules on a capsule filling machine.

Example 28

Suppositories containing 100 mg of active substance

1 suppository contains

active substance 100.0 mg

polyethylene glycol (M.M. 1500) 600.0 mg

polyethylene glycol (M.M. 6000) 460.0 mg

polyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

Method:

Polyethylene glycol dissolved together with polyethylene sorbitan monostearate. At 40°C, the basic active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly cooled molds for suppositories.

Claims (13)

1. Benzimidazoles of the general formula [image] indicated by that Ar represents a phenylene or naphthylene group optionally substituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted in the carbon base structure with a C1-3-alkyl group, A represents a C1-3-alkylene group, B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted with a C1-3-alkyl group where the alkyl group can be mono- or disubstituted with a carboxy group, Ra represents R1-CO-C3-5-cycloalkyl group in which R1 represents a C1-3-Alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group, where each alkyl group can be substituted with a carboxy group, a 4- to 7-membered cycloalkylenimine or cycloalkenylene-imino group, which can be substituted with a hydroxy group or can be one or two C1-3-alkyl groups, while one alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-Alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylamino- carbonyl, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino-carbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy -C1-3-alkyl)-aminocarbonylamino, 3-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3- (carboxy-C1-3-alkyl)-aminocarbonylamino group, 4- to 7-membered cycloalkenylenimino group substituted with a hydroxy group, a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms, morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydropiperidino or pyrrole-1-yl group, R2-CX-C3-5-cycloalkyl group in which R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, where the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains an imino group optionally substituted with a C1-3-alkyl group, an oxygen or sulfur atom or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent can be substituted with carboxy, by a carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and X represents an oxygen atom, C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-(C1-3-alkyl) -C2-4-alkanoylhydrazino or C1-3-alkylidene group, each of which can be substituted in the alkyl or alkanoyl part or in the alkyl and alkanoyl groups with a carboxy group, C1-3-alkyl or C3-5-cycloalkyl group substituted with an imidazole or imidazolone group in which the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, wherein the substituents can be identical or different and one of the aforementioned alkyl substituents can simultaneously be substituted with a carboxy group or may be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-C1-3-alkyl-amino or di- (C1-3-alkyl)-amino group, i the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and additionally, the phenyl or pyridine ring can be fused to the aforementioned imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with a carboxy group, C1-4-alkyl group which is substituted with C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3- alkyl group i with an isoxazolidinylcarbonyl group optionally substituted with a C1-3-alkyl group, with pyrroline-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrole-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylamino-carbonyl, di-( C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time any alkyl group or alkyl substituent in the above-mentioned C1 -3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms in the C1-4-alkyl group can be completely or partially replaced with fluorine atoms, whereby R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i R4 represents a hydrogen atom, C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1 -3-alkyl-Y3 group or R3 and R4 together with the nitrogen atom between them represent a 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, wherein Y1 represents a carbon-carbon bond, an oxygen atom, sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH-group and Y2 represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, where the carbonyl group in the -NH-CO- group is attached to the nitrogen atom of the R3NR4- group, and each of the imino groups, which derive from the definition of the groups yi and Y2, may be additionally substituted with a C1-3-alkyl or carboxy-C1-3-alkyl group, C1-3-alkyl or C3-5-cycloalkyl group substituted with R5NR6- group where R5 represents a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted with a C2-4-alkanoyl or C5-7-cycloalkanoyl group and with a C1-3-alkyl group substituted with a chlorine, bromine or iodine atom, Rb represents a hydrogen atom or a C1-3-alkyl group and Re represents a cyano group or an amidino group optionally substituted with one or two C1-3-alkyl groups, their tautomers, stereoisomers, their mixtures, their prodrugs, their derivatives that instead of a carboxy group contain a group that has a negative charge under physiological conditions, and their salts. 2. Benzimidazoles of the general formula [image] indicated by that A represents a C1-3-alkylene group, B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted with a C1-3-alkyl group, where the alkyl group can be mono- or disubstituted with a carboxy group, Ra represents R1-CO-C3-5-cycloalkyl group in which R1 represents a C1-3-Alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group, where each alkyl group can be substituted with a carboxy group, 4- to 7-membered cycloalkyleneimino or cycloalkenylene-imino group that can be substituted with one or two C1-3-alkyl groups, while the alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3 -Alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3- alkyl)-N-(carboxy-C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3 -(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonyl -amino group, 4- to 7-membered cycloalkenylenimino group substituted with a hydroxy group, a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms, morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydro-piperidino or pyrrole-1-yl group, R2-CX-C3-5-cycloalkyl group in which R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, in which the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains imino a group optionally substituted with a C1-3-alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent can be substituted with by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and X represents an oxygen atom, C1-3-alkylimino, C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-hydrazino, C2-4-alkanoyl-hydrazino, N-(C1-3- alkyl)-C2-4-alkanoylhydrazino or C1-3-alkylidene group, each of which can be substituted in the alkyl or alkanoyl part or in the alkyl and alkanoyl groups with a carboxy group, C1-3-alkyl or C3-5-cycloalkyl group substituted with an imidazole or imidazolone group in which the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3 -alkyl groups, where the substituents can be identical or different and one of the aforementioned alkyl substituents can be simultaneously substituted with a carboxy group or can be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylaniino, N -(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and additionally, the phenyl or pyridine ring can be fused to the aforementioned imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with a carboxy group, C1-4-alkyl group which is substituted with C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4- or R3NR4-C1-3- alkyl group i with an isoxazolidinylcarbonyl group optionally substituted with a C1-3-alkyl group, with pyrroline-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrole-1-yl-carbonyl, carboxy, aminocarbonyl, C1-3-alkylamino-carbonyl, di-( C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time any alkyl group or alkyl substituent in the above-mentioned C1 -3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms in the C1-4-alkyl group can be completely or partially replaced with fluorine atoms, where R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i R4 represents a hydrogen atom, C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1 -3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom between them represent a 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group where Y1 represents a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- group and Y2 represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, where the carbonyl group in the NH-CO- group is connected to the nitrogen atom of the R3NR4- group, and each imino group obtained by the definition of the groups Y1 and Y2 can be additionally substituted with a C1-3-alkyl or carboxy-C1-3-alkyl group, C1-3-alkyl or C3-5-cycloalkyl group substituted with R5NR6- group in which R5 represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkylcarbonyl group, a C1-3-alkyl group which is substituted with a C2-4-alkanoyl or C5-7-cycloalkanoyl group and with a C1-3-alkyl group substituted with chlorine, chromium or with an iodine atom, Rb represents a hydrogen atom or a C1-3-alkyl group and Rc represents a cyano group or an amidino group that can be substituted with a hydroxy group, with one or two C1-3-alkyl groups, or with one or two C1-8-alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in the definition of the aforementioned groups can also be substituted with a group that can be cleaved in vivo, their tautomers, stereoisomers and their salts. 3. Benzimidazoles of the general formula la according to claim 2, characterized in that A represents a C1-3-alkylene group, B represents an oxygen atom, methylene, imino or N-(C1-3-alkyl)-imino group in which the alkyl group can be substituted with a carboxy group, Ra represents a C3-5-cycloalkyl group substituted with an R1-CO group in position 1, whereby R1 represents a C1-3-Alkoxy, amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group in which each alkyl group can be substituted with a carboxy group, a 4- to 7-membered cycloalkylenimine group that can be substituted with a hydroxy group or with one or two C1-3-alkyl groups, while the alkyl substituent can be simultaneously substituted with hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3 -Alkoxy, carboxy-C1-3-alkylamino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, carboxy-C1-3-alkylaminocarbonyl, N-(C1-3- alkyl)-N-(carboxy-C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino, 3 -(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-C1-3-alkyl)-aminocarbonyl -amino group, a 5- to 7-membered cycloalkylenimine group optionally substituted with a C1-3-alkyl group, to which the phenyl ring is fused via two adjacent carbon atoms, morpholino, piperazino, N-(C1-3-alkyl)-piperazino, pyrroline, 3,4-dehydro-piperidino or pyrrole-1-yl group, C3-5-cycloalkyl group substituted in position 1 with R2-CX- group, where R2 represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains imino a group optionally substituted with a C1-3-alkyl group, oxygen or a sulfur atom, or an imino group optionally substituted with a C1-3-alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted with by a carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, and X represents an oxygen atom, a C1-3-alkylimino, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which can be substituted in an alkyl or alkanoyl group with a carboxy group, C1-3-alkyl group substituted in position l with imidazole or imidazolone group where the imidazole ring may be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, whereby the substituents may be identical or different and one of the aforementioned alkyl substituents may simultaneously be substituted with a carboxy group or may be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-3-alkanoyl)-C1-3-alkylamino or di-(C1 -3-alkyl)-amino group, i the imidazolone ring can be substituted with a C1-3-alkyl group, while the alkyl substituent can be substituted with a carboxy group or in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4- alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and additionally, the phenyl or pyridine ring can be fused to the aforementioned imidazole or imidazolone ring via two adjacent carbon atoms, an imidazolidin-2,4-dion-5-yl group that can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with a carboxy group, C1-4-alkyl group which is substituted in position 1 with R3NR4- or R3NR4-C1-3-alkyl group and with pyrrolinocarbonyl, 2,3-dehydro-piperidino-carbonyl, imidazol-1-yl-carbonyl, carboxy, amino-carbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, isoxazolidin-1-yl -carbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, while in the above-mentioned groups the cycloalkylenimino group can be substituted with one or two C1-3-alkyl groups and at the same time each alkyl group or alkyl substituent in the above-mentioned C1-3-alkylaminocarbonyl, di -(C1-3-alkyl)-aminocarbonyl or cycloalkyleniminocarbonyl group can be substituted with a carboxy group, and the remaining hydrogen atoms of the C1-3-alkyl group can be completely or partially replaced with fluorine atoms, whereby R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i R4 represents a hydrogen atom, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom located between them form a 4- to 7-membered cycloalkylenimine group optionally substituted in position l with a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, where Y2 represents a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, where the carbonyl group in the -NH-CO- group is connected to the nitrogen atom of the R3NR4 group and the imino group formed by the definition of the Y2 group can be additionally substituted with C1- 3-alkyl or carboxy-C1-3-alkyl group, C1-3-alkyl or C3-5-cycloalkyl group substituted in position l with R5NR6- group, where R5 represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and R6 represents a C1-3-alkyl, carboxy-C1-3-alkyl or carboxy-C1-3-alkyl carbonyl group, C1-3-alkyl group which is substituted with C1-3-alkanoyl or C5-7-cycloalkanoyl group and with C1-3-alkyl group substituted with chlorine, bromine or iodine atom, Rb represents a C1-3-alkyne group and Rc represents an amidino group which can be substituted with 2,2,2-trichloroethoxycarbonyl, C1-8- alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or a benzoyl group, while the benzoyl group can be mono- or disubstituted with fluorine, chlorine, bromine or by an iodine atom, with a C1-3-alkyl or C1-3-alkoxy group and the substituents may be identical or different, their C1-3-alkanol esters, tautomers, stereoisomers and their salts. 4. Benzimidazoles of the general formula Ia according to claim 2, characterized in that A represents a methylene group, B represents an oxygen atom or an imino group, Ra represents a cyclopropyl group substituted with the group R1-CO- in position 1, where R1 represents a pyrrolidino or piperidino group optionally substituted with a methyl or ethyl group, wherein each methyl or ethyl group can be substituted with carboxy, carboxy-C1-3- alkoxy, carboxy-C1-3-alkylamino or N-(C1-3- alkyl)-carboxy-C1-3-alkylamino group, cyclopropyl group substituted in position l with the group R2-CX-, in which R2 represents a phenyl, pyridyl, pyrazolyl group optionally substituted with a C1-3-alkyl group and X represents an oxygen atom, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which is a substituent in the alkyl or alkoxy part with a carboxy group, C1-2-alkyl group substituted in position l with an imidazole group, where the imidazole ring can be substituted with a phenyl or carboxy group and with one or two C1-3-alkyl groups or with one, two or three C1-3-alkyl groups, whereby the substituents may be identical or different and one of the aforementioned alkyl substituents may be simultaneously substituted with a carboxy group or may be substituted in position 2 or 3 with amino, C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4 -alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while additionally the phenyl or pyridine ring can be fused to the aforementioned imidazole ring via two adjacent carbon atoms, C1-2-alkyl substituted in position l with a benzimidazolon-1-yl group, while the imidazolone ring can be substituted with a methyl or ethyl group optionally substituted with a carboxy group, methyl or ethyl group which is substituted in position 1 with R3NR4- or R3NR4-C1-3-alkyl group and with a di-(C1-3-alkyl)-aminocarbonyl group, with an isoxazolidin-1-yl-carbonyl group, with a pyrrolidino-carbonyl or piperidino-carbonyl group substituted with a C1-3-alkyl group, while in the aforementioned groups each alkyl group or the alkyl substituent in the above-mentioned groups can be substituted with a carboxy group, whereby R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i R4 represents a hydrogen atom, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R3 and R4 together with the nitrogen atom located between them form a 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy group, where Y2 represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with a C1-3-alkyl group, C1-2-alkyl group substituted in position 1 with R5NR6- with blackberry, where R5 represents a pyridinyl, phenyl, carbonyl or phenylsulfonyl group and R6 represents a C1-3-alkyl or carboxy-C1-3-alkyl group, an n-propyl group substituted in position 3 with a chlorine atom, which is substituted in position 1 with a cyclopentyl-carbonyl group, a cyclopropyl group substituted in position l with a cyclopentylamino group, which is substituted on the nitrogen atom with a carboxy-C1-3-alkylcarbonyl group, Rb represents a methyl group and Rc represents an amidino group which, if necessary, can be substituted with a C1-8-alkoxycarbonyl, acetoxy-methyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, their C1-3-alkanol esters, tautomers, stereoisomers and their salts. 5. Benzimidazoles of the general formula Ia according to claim 2, characterized in that A represents a methylene group, B represents the imino group, Ra represents a cyclopropyl group substituted with R1-CO- group in position 1, where R1 represents a pyrrolidino or piperidino group optionally substituted with a methyl or ethyl group, wherein each methyl or ethyl group can be substituted with carboxy, carboxy-C1-3- alkoxy, carboxy-C1-3-alkylamino or with N-(C1- 3-alkyl)-carboxy-C1-3-alkylamino group, a cyclopropyl group substituted in position l with an R2-CX group, in which R2 represents a phenyl, pyridyl, pyrazolyl group optionally substituted with a C1-3-alkyl group and X represents an oxygen atom, a C1-3-alkoxyimino or a C1-3-alkylidene group, each of which is substituted in the alkyl or alkoxy part with a carboxy group, C1-2-alkyl group substituted in position 1 with an imidazole group, whereby the imidazole ring can be substituted with one to three methyl groups or with two methyl groups and one ethyl group, while additionally one of the above-mentioned methyl or ethyl substituents can be substituted at the same time with a carboxy group, methyl or ethyl group which is substituted in position l with R3NR4- or R3NR4-CH2- group i with di-(C1-3-alkyl)-aminocarbonyl, with pyrrolidino-carbonyl or piperidinocarbonyl group optionally substituted with a C1-3-alkyl group, while in the aforementioned groups each alkyl group or alkyl substituent can be substituted with a carboxy group, where R3 represents a hydrogen atom or a C1-3-alkyl group optionally substituted with a carboxy group i R4 represents a C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group, giving Y2 represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with a C1-3-alkyl group, Rb represents a methyl group and RC represents an amidino group which, if necessary, can be substituted with a C1-8-alkoxycarbonyl, acetoxy-methyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, their C1-3-alkanol esters, tautomers, stereoisomers and their salts. 6. Benzimidazoles of the general formula la according to claim 2, characterized in that the Ra group is in position 5, their tautomers, stereoisomers and their salts. 7. Compounds of the general formula 1a, indicated by the fact that they are the following compounds: (a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxymethyloxyimino)methylene]-cyclopropyl]-benzimidazole, (c) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, (d) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole, (e) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl]-benzimidazole, (f) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and (g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, and their C1-3-alkanol esters, N-(C1-8-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines, tautomers, ethereoisomers and their salts. 8. A compound characterized by the fact that it is 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole, and its C1-3-alkanol esters, N-(C1-8-Alkoxycarbonyl), N-benzyl-oxycarbonyl and N-benzoyl-amidines, tautomers, ethereoisomers and salts. 9. Physiologically acceptable salts of compounds according to claims 1 to 8, characterized in that Rc represents one of the amidino groups mentioned in claims 1 to 8. 10. Pharmaceutical preparations, indicated by the fact that they contain at least one compound according to claims 1 to 8, where Rc represents one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, if necessary together with one or more inert carriers and/ or dilution agents. 11. The use of a compound according to at least one of claims 1 to 8, where Rc represents one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, characterized in that it is used for the production of a pharmaceutical preparation with the effect of prolonging thrombin time, by inhibiting thrombin and by inhibiting serine-related proteases. 12. A process for the production of a pharmaceutical preparation according to claim 10, characterized in that the compound according to at least one of claims 1 to 8, where Rc represents one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, by a non-chemical method install in one or more inert carriers and/or dilution agents. 13. Process for the production of compounds according to claims 1 to 9, characterized in that a) for the preparation of the compound of the general formula I in which Rc represents the cyano group: cyclize the compound of the general formula [image] which, as necessary, was formed in the reaction mixture, in which formula Ra, Rb, Ar, and B are defined as in claims 1 to 8, Z1 and Z2, which may be identical or different, represent amino, hydroxy or mercapto groups optionally substituted with alkyl groups having from 1 to 6 carbon atoms or Z1 and Z2 together represent an oxygen or sulfur atom, an imino group optionally substituted with an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, or b) for the preparation of a compound of the general formula I in which Ra represents R2-CX' -C3-5-cycloalkylene group, where R2 is defined as previously, and S' represents one of the imino groups mentioned earlier for X, a compound of the general formula [image] in which they are Rb, Rc, Ar, and B are defined as in claims 1 to 8, and Ra represents an R2-CO-C3-5-cycloalkylene group, where is R 2 defined as in claims 1 to 8, reacts with an amine of the general formula H2X' (V) , where X' represents one of the imino groups mentioned earlier for X, or c) for the preparation of a compound of the general formula I in which Ra represents a R2-CX"-C1-3-cycloalkylene group, where R2 is defined as previously, and X" represents one of the alkylidene groups mentioned earlier for X, a compound of the general formula [image] in which they are Rb, Rc, Ar, and B are defined as in claims 1 to 8, and Ra' represents an R2-CO-C3-5-cycloalkylene group, where is R2 defined as in claims 1 to 8, reacts with a phosphone of the general formula Z3-HX" (VI) , where X" represents one of the alkylidene groups mentioned for X in claims 1 to 8, i Z 3 represents a triphenylphosphono or a di-(C 1-3 -alkoxy)-phosphono group, or d) for the preparation of a compound of the general formula I in which Rc represents an amidino group that can be substituted with one or two C1-3-alkyl groups: a compound of the general formula [image] which, if necessary, was formed in the reaction mixture, what formula are they in Ra, Rb, Ar, and B are defined as in claims 1 to 8, and Z4 is alkoxy or aralkyl, alkylthio or aralkylthio group, reacts with an amine of the general formula H - R7MR8 (VIII) , where R7 and R8, which may be identical or different, each represent a hydrogen atom or a C1-3-alkyl group, or with salts thereof, or e) for the preparation of a compound of general formula I in which Ra represents an imidazolidin-2,4-dion-5-yl group, which can be substituted with one or two C1-3-alkyl groups, while at the same time the alkyl substituent can be substituted with carboxy or with a C1-3-Alkoxycarbonyl group, the compound of the general formula is cyclized [image] which, if necessary, disappeared in the reaction mixture, what formula are they in RB, Ar, and B as defined in claims 1 to 8, i Ra'' represents an aminocarbonylamino group substituted in position 3 with a C1-3-alkoxycarbonyl-C1-3-alkyl group, or f) for the preparation of a compound of the general formula I in which Rc represents a hydroxyamidino group: nitrile of the general formula [image] in which they are Ra, Rb, Ar and B defined as in claims 1 to 8, react with hydroxylamine or its salt, or g) to prepare a compound of the general formula I in which Ra contains a carboxy group and Rc is defined as in claims 1 to 8, and Ra is defined as in claims 1 to 8, and Rc represents an amidino group optionally substituted with a hydroxy group or with one or two C1-3-alkyl groups, a compound of the general formula [image] what formula are they in Rb, Ar, and B as defined in claims 1 to 8, and Ra' " and Rc' have the meaning given to Ra and Rc in claims 1 to 8, provided that Ra contains a group which can be converted to a carboxy group by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and Rc is defined as in claims 1 to 8, or Rc represents a group which, if necessary, can be converted into an amidino group substituted with a hydroxy group or with one or two C1-3-alkyl groups, with Ra defined as in claims 1 to 8, is converted by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group and Rc is defined as in claims 1 to 8, or Ra is defined as in claims 1 to 8, and Rc represents an amidino group optionally substituted with a hydroxy group or with one or two C1-3-alkyl groups, or h) for the preparation of a compound of the general formula I in which Rc represents an amidino group that is substituted with one or two C1-8-alkoxycarbonyl groups or with a group that can be cleaved in vivo, of a compound of the general formula I [image] in which they are Ra, Rb, Ar, and B as defined in claims 1 to 8, i Rc" represents an amidino group, it reacts with a compound of the general formula Z5-R9(XIII), where R9 represents a C1-8-alkoxycarbonyl group or an acyl group of one of the previously mentioned groups that can be cleaved in vivo and Z5 represents a nucleophilic leaving group, i then, if desired, if the thus obtained compound of the general formula I contains (R3NR4)-C1-3-alkyl group in which at least one of the groups R3 or R4 represents a hydrogen atom, it is converted with the appropriate isocyanate or carbamoyl halide into the corresponding urea compound of the general formula I, and/or if the thus obtained compound of the general formula I contains an NH2-C1-3-alkyl group, it can be converted with a suitable acrylic acid ester into the corresponding 2-(C1-3-alkoxy-carbonyl)-ethyl compound of the general formula I, and/or if the thus obtained compound of the general formula I contains (R3NR4)-C1-3-alkyl group in which each of R3 and R4 represents a hydrogen atom, it can be converted with a suitable dihaloalkane into the corresponding compound of the general formula I in which R3 and R4 together with nitrogen with the atom located between them represent a corresponding 4- to 7-membered cycloalkylenimine group, and/or if a compound of the general formula I in which Rc represents an amidino group is thus obtained, it can be converted by reaction with a haloacetic acid derivative and then by hydrolysis and decarboxylation into the corresponding amidino compound substituted with one or two methyl groups, and/or if a compound of the general formula I is thus obtained in which Rc represents a hydroxyamidino group, it can be converted into the corresponding amidino compound by catalytic hydrogenation, and/or if a compound of the general formula I is thus obtained in which Ra contains a carboxy group, it can be converted into the corresponding ester by esterification, and/or the protecting group, used to protect reactive groups during reactions, is cleaved off, and/or the thus obtained compound of the general formula I is separated into its stereoisomers, and/or the thus obtained compound of the general formula I is translated into its salts, more specifically, for pharmaceutical use, into its physiologically acceptable salts with an inorganic or organic acid or base.